2024 |
Meyer B, Stirzaker C, Ramkomuth S, Harvey K, Chan B, Lee CS, et al., 'Detailed DNA methylation characterisation of phyllodes tumours identifies a signature of malignancy and distinguishes phyllodes from metaplastic breast carcinoma', JOURNAL OF PATHOLOGY, 262 480-494 (2024) [C1]
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2024 |
Hess JL, Mattheisen M, Greenwood TA, Tsuang MT, Edenberg HJ, Holmans P, et al., 'A polygenic resilience score moderates the genetic risk for schizophrenia: Replication in 18,090 cases and 28,114 controls from the Psychiatric Genomics Consortium', American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 195 (2024) [C1]
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2024 |
Reay WR, Clarke E, Eslick S, Riveros C, Holliday EG, McEvoy MA, et al., 'Using Genetics to Inform Interventions Related to Sodium and Potassium in Hypertension.', Circulation, 149 1019-1032 (2024) [C1]
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2024 |
Georgiadis F, Larivière S, Glahn D, Hong LE, Kochunov P, Mowry B, et al., 'Connectome architecture shapes large-scale cortical alterations in schizophrenia: a worldwide ENIGMA study.', Mol Psychiatry, (2024) [C1]
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2024 |
Pietrzak S, Marciniak W, Derkacz R, Matuszczak M, Kiljanczyk A, Baszuk P, et al., 'Correlation between Selenium and Zinc Levels and Survival among Prostate Cancer Patients', Nutrients, 16 527-527
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2024 |
Nagarajan P, Winkler TW, Bentley AR, Miller CL, Kraja AT, Schwander K, et al., 'A Large-Scale Genome-Wide Study of Gene-Sleep Duration Interactions for Blood Pressure in 811,405 Individuals from Diverse Populations.', medRxiv, (2024)
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2024 |
Kiltschewskij DJ, Reay WR, Geaghan MP, Atkins JR, Xavier A, Zhang X, et al., 'Alteration of DNA Methylation and Epigenetic Scores Associated With Features of Schizophrenia and Common Variant Genetic Risk.', Biological psychiatry, 95 647-661 (2024) [C1]
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2024 |
Paul CL, Verrills NM, Ackland S, Scott R, Goode S, Thomas A, et al., 'The impact of a regionally based translational cancer research collaborative in Australia using the FAIT methodology.', BMC Health Serv Res, 24 320 (2024) [C1]
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2024 |
Petit J, Carroll G, Zhao J, Pockney P, Scott RJ, 'The Prognostic Utility of KRAS Mutations in Tissue and Circulating Tumour DNA in Colorectal Cancer Patients', Gastroenterology Insights, 15 107-121 [C1]
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2024 |
Koromina M, Ravi A, Panagiotaropoulou G, Schilder BM, Humphrey J, Braun A, et al., 'Fine-mapping genomic loci refines bipolar disorder risk genes.', medRxiv, (2024)
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2024 |
Boen R, Kaufmann T, van der Meer D, Frei O, Agartz I, Ames D, et al., 'Beyond the Global Brain Differences: Intraindividual Variability Differences in 1q21.1 Distal and 15q11.2 BP1-BP2 Deletion Carriers.', Biol Psychiatry, 95 147-160 (2024) [C1]
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2023 |
Petit J, Carroll G, Zhao J, Roper E, Pockney P, Scott RJ, 'Evaluation of epigenetic methylation biomarkers for the detection of colorectal cancer using droplet digital PCR', Scientific Reports, 13 (2023) [C1]
Colorectal cancer (CRC) is the third most common cancer worldwide. Screening programs allow early diagnosis and have improved the clinical management of this disease. Aberrant DNA... [more]
Colorectal cancer (CRC) is the third most common cancer worldwide. Screening programs allow early diagnosis and have improved the clinical management of this disease. Aberrant DNA methylation is increasingly being explored as potential biomarkers for many types of cancers. In this study we investigate the methylation of ten target genes in 105 CRC and paired normal adjacent colonic tissue samples using a MethylLight droplet digital PCR (ML-ddPCR) assay. Receiver operator characteristic (ROC) curves were used to determine the diagnostic performance of all target genes individually and in combination. All 515 different combinations of genes showed significantly higher levels of methylation in CRC tissue. The combination of multiple target genes into a single test generally resulted in greater diagnostic accuracy when compared to single target genes. Our data confirms that ML-ddPCR is able to reliably detect significant differences in DNA methylation between CRC tissue and normal adjacent colonic tissue in a specific selection of target genes.
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2023 |
Constantinides C, Han LKM, Alloza C, Antonucci LA, Arango C, Ayesa-Arriola R, et al., 'Brain ageing in schizophrenia: evidence from 26 international cohorts via the ENIGMA Schizophrenia consortium.', Mol Psychiatry, 28 1201-1209 (2023) [C1]
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2023 |
Bain NL, Koulouris N, Scott R, Buckman M, Goel H, 'A familial rearrangement resulting in pure duplication of distal 19p13.3', Clinical Dysmorphology, 32 184-188 (2023) [C1]
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2023 |
Jamaluddin MFB, Nagendra PB, Ko Y-A, Bajwa P, Scott RJ, Nahar P, Tanwar PS, 'Prevalence and clinical significance of co-existing mutations in MED12 and FH in uterine fibroids of Australian women', Frontiers in Reproductive Health, 5 [C1]
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2023 |
Morra A, Schreurs MAC, Andrulis IL, Anton-Culver H, Augustinsson A, Beckmann MW, et al., 'Association of the CHEK2 c.1100delC variant, radiotherapy, and systemic treatment with contralateral breast cancer risk and breast cancer-specific survival', Cancer Medicine, 12 16142-16162 (2023) [C1]
Background: Breast cancer (BC) patients with a germline CHEK2 c.1100delC variant have an increased risk of contralateral BC (CBC) and worse BC-specific survival (BCSS) compared to... [more]
Background: Breast cancer (BC) patients with a germline CHEK2 c.1100delC variant have an increased risk of contralateral BC (CBC) and worse BC-specific survival (BCSS) compared to non-carriers. Aim: To assessed the associations of CHEK2 c.1100delC, radiotherapy, and systemic treatment with CBC risk and BCSS. Methods: Analyses were based on 82,701 women diagnosed with a first primary invasive BC including 963 CHEK2 c.1100delC carriers; median follow-up was 9.1 years. Differential associations with treatment by CHEK2 c.1100delC status were tested by including interaction terms in a multivariable Cox regression model. A multi-state model was used for further insight into the relation between CHEK2 c.1100delC status, treatment, CBC risk and death. Results: There was no evidence for differential associations of therapy with CBC risk by CHEK2 c.1100delC status. The strongest association with reduced CBC risk was observed for the combination of chemotherapy and endocrine therapy [HR (95% CI): 0.66 (0.55¿0.78)]. No association was observed with radiotherapy. Results from the multi-state model showed shorter BCSS for CHEK2 c.1100delC carriers versus non-carriers also after accounting for CBC occurrence [HR (95% CI): 1.30 (1.09¿1.56)]. Conclusion: Systemic therapy was associated with reduced CBC risk irrespective of CHEK2 c.1100delC status. Moreover, CHEK2 c.1100delC carriers had shorter BCSS, which appears not to be fully explained by their CBC risk.
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2023 |
Omlor W, Rabe F, Fuchs S, Cecere G, Homan S, Surbeck W, et al., 'Estimating multimodal brain variability in schizophrenia spectrum disorders: A worldwide ENIGMA study.', bioRxiv, (2023)
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2023 |
White C, Scott RJ, Paul C, Ackland S, 'Reply to "Implementation of DPYD Genotyping in Admixed American Populations: Brazil as a Model Case"', CLINICAL PHARMACOLOGY & THERAPEUTICS, 114 25-25 (2023)
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2023 |
Young M-A, Yanes T, Cust AE, Dunlop K, Limb S, Newson AJ, et al., 'Human Genetics Society of Australasia Position Statement: Use of Polygenic Scores in Clinical Practice and Population Health.', Twin Res Hum Genet, 26 40-48 (2023) [C1]
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2023 |
Schijven D, Postema MC, Fukunaga M, Matsumoto J, Miura K, de Zwarte SMC, et al., 'Large-scale analysis of structural brain asymmetries in schizophrenia via the ENIGMA consortium.', Proc Natl Acad Sci U S A, 120 e2213880120 (2023) [C1]
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2023 |
Weigner J, Billings R, Scott RJ, King S, 'The utilisation of digital droplet PCR to enhance the diagnosis of bladder and pancreaticobiliary tumours in cytology specimens.', Diagn Cytopathol, 51 511-518 (2023) [C1]
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2023 |
Xavier A, Campagna MP, Maltby VEE, Kilpatrick T, Taylor BVV, Butzkueven H, et al., 'Interferon beta treatment is a potent and targeted epigenetic modifier in multiple sclerosis', FRONTIERS IN IMMUNOLOGY, 14 (2023) [C1]
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2023 |
Revelas M, Thalamuthu A, Zettergren A, Oldmeadow C, Najar J, Seidu NM, et al., 'High polygenic risk score for exceptional longevity is associated with a healthy metabolic profile.', Geroscience, 45 399-413 (2023) [C1]
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2023 |
Morra A, Mavaddat N, Muranen TA, Ahearn TU, Allen J, Andrulis IL, et al., 'The impact of coding germline variants on contralateral breast cancer risk and survival', American Journal of Human Genetics, 110 475-486 (2023) [C1]
Evidence linking coding germline variants in breast cancer (BC)-susceptibility genes other than BRCA1, BRCA2, and CHEK2 with contralateral breast cancer (CBC) risk and breast canc... [more]
Evidence linking coding germline variants in breast cancer (BC)-susceptibility genes other than BRCA1, BRCA2, and CHEK2 with contralateral breast cancer (CBC) risk and breast cancer-specific survival (BCSS) is scarce. The aim of this study was to assess the association of protein-truncating variants (PTVs) and rare missense variants (MSVs) in nine known (ATM, BARD1, BRCA1, BRCA2, CHEK2, PALB2, RAD51C, RAD51D, and TP53) and 25 suspected BC-susceptibility genes with CBC risk and BCSS. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated with Cox regression models. Analyses included 34,401 women of European ancestry diagnosed with BC, including 676 CBCs and 3,449 BC deaths; the median follow-up was 10.9 years. Subtype analyses were based on estrogen receptor (ER) status of the first BC. Combined PTVs and pathogenic/likely pathogenic MSVs in BRCA1, BRCA2, and TP53 and PTVs in CHEK2 and PALB2 were associated with increased CBC risk [HRs (95% CIs): 2.88 (1.70¿4.87), 2.31 (1.39¿3.85), 8.29 (2.53¿27.21), 2.25 (1.55¿3.27), and 2.67 (1.33¿5.35), respectively]. The strongest evidence of association with BCSS was for PTVs and pathogenic/likely pathogenic MSVs in BRCA2 (ER-positive BC) and TP53 and PTVs in CHEK2 [HRs (95% CIs): 1.53 (1.13¿2.07), 2.08 (0.95¿4.57), and 1.39 (1.13¿1.72), respectively, after adjusting for tumor characteristics and treatment]. HRs were essentially unchanged when censoring for CBC, suggesting that these associations are not completely explained by increased CBC risk, tumor characteristics, or treatment. There was limited evidence of associations of PTVs and/or rare MSVs with CBC risk or BCSS for the 25 suspected BC genes. The CBC findings are relevant to treatment decisions, follow-up, and screening after BC diagnosis.
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2023 |
Petit J, Carroll G, Williams H, Pockney P, Scott RJ, 'Evaluation of a Multi-Gene Methylation Blood-Test for the Detection of Colorectal Cancer', Medical Sciences, 11 60-60 [C1]
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2023 |
Li N, Zethoven M, McInerny S, Healey E, DeSilva D, Devereux L, et al., 'Contribution of large genomic rearrangements in
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2023 |
Wang X, Kho PF, Ramachandran D, Bafligil C, Amant F, Goode EL, et al., 'Multi-trait genome-wide association study identifies a novel endometrial cancer risk locus that associates with testosterone levels', iScience, 26 (2023) [C1]
To detect novel endometrial cancer risk variants, we leveraged information from endometrial cancer risk factors in a multi-trait GWAS analysis. We first assessed causal relationsh... [more]
To detect novel endometrial cancer risk variants, we leveraged information from endometrial cancer risk factors in a multi-trait GWAS analysis. We first assessed causal relationships between established and suspected endometrial cancer risk factors, and endometrial cancer using Mendelian randomization. Following multivariable analysis, five independent risk factors (waist circumference, testosterone levels, sex hormone binding globulin levels, age at menarche, and age at natural menopause) were included in a multi-trait Bayesian GWAS analysis. We identified three potentially novel loci that associate with endometrial cancer risk, one of which (7q22.1) replicated in an independent endometrial cancer GWAS dataset and was genome-wide significant in a meta-analysis. This locus may affect endometrial cancer risk through altered testosterone levels. Consistent with this, we observed colocalization between the signals for endometrial cancer risk and expression of CYP3A7, a gene involved in testosterone metabolism. Thus, our findings suggest opportunities for hormone therapy to prevent or treat endometrial cancer.
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2023 |
Maltby V, Xavier A, Ewing E, Campagna M-P, Sampangi S, Scott RJ, et al., 'Evaluation of Cell-Specific Epigenetic Age Acceleration in People With Multiple Sclerosis.', Neurology, 101 e679-e689 (2023) [C1]
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2023 |
Hsu YHH, Pintacuda G, Liu R, Nacu E, Kim A, Tsafou K, et al., 'Using brain cell-type-specific protein interactomes to interpret neurodevelopmental genetic signals in schizophrenia', iScience, 26 (2023) [C1]
Genetics have nominated many schizophrenia risk genes and identified convergent signals between schizophrenia and neurodevelopmental disorders. However, functional interpretation ... [more]
Genetics have nominated many schizophrenia risk genes and identified convergent signals between schizophrenia and neurodevelopmental disorders. However, functional interpretation of the nominated genes in the relevant brain cell types is often lacking. We executed interaction proteomics for six schizophrenia risk genes that have also been implicated in neurodevelopment in human induced cortical neurons. The resulting protein network is enriched for common variant risk of schizophrenia in Europeans and East Asians, is down-regulated in layer 5/6 cortical neurons of individuals affected by schizophrenia, and can complement fine-mapping and eQTL data to prioritize additional genes in GWAS loci. A sub-network centered on HCN1 is enriched for common variant risk and contains proteins (HCN4 and AKAP11) enriched for rare protein-truncating mutations in individuals with schizophrenia and bipolar disorder. Our findings showcase brain cell-type-specific interactomes as an organizing framework to facilitate interpretation of genetic and transcriptomic data in schizophrenia and its related disorders.
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2023 |
Mueller SH, Lai AG, Valkovskaya M, Michailidou K, Bolla MK, Wang Q, et al., 'Aggregation tests identify new gene associations with breast cancer in populations with diverse ancestry', Genome Medicine, 15 (2023) [C1]
Background: Low-frequency variants play an important role in breast cancer (BC) susceptibility. Gene-based methods can increase power by combining multiple variants in the same ge... [more]
Background: Low-frequency variants play an important role in breast cancer (BC) susceptibility. Gene-based methods can increase power by combining multiple variants in the same gene and help identify target genes. Methods: We evaluated the potential of gene-based aggregation in the Breast Cancer Association Consortium cohorts including 83,471 cases and 59,199 controls. Low-frequency variants were aggregated for individual genes¿ coding and regulatory regions. Association results in European ancestry samples were compared to single-marker association results in the same cohort. Gene-based associations were also combined in meta-analysis across individuals with European, Asian, African, and Latin American and Hispanic ancestry. Results: In European ancestry samples, 14 genes were significantly associated (q < 0.05) with BC. Of those, two genes, FMNL3 (P = 6.11 × 10-6) and AC058822.1 (P = 1.47 × 10-4), represent new associations. High FMNL3 expression has previously been linked to poor prognosis in several other cancers. Meta-analysis of samples with diverse ancestry discovered further associations including established candidate genes ESR1 and CBLB. Furthermore, literature review and database query found further support for a biologically plausible link with cancer for genes CBLB, FMNL3, FGFR2, LSP1, MAP3K1, and SRGAP2C. Conclusions: Using extended gene-based aggregation tests including coding and regulatory variation, we report identification of plausible target genes for previously identified single-marker associations with BC as well as the discovery of novel genes implicated in BC development. Including multi ancestral cohorts in this study enabled the identification of otherwise missed disease associations as ESR1 (P = 1.31 × 10-5), demonstrating the importance of diversifying study cohorts.
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2023 |
Lim BWX, Li N, Mahale S, McInerny S, Zethoven M, Rowley SM, et al., 'Somatic inactivation of breast cancer predisposition genes in tumors associated with pathogenic germline variants.', J Natl Cancer Inst, 115 181-189 (2023) [C1]
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2023 |
Challakere Ramaswamy VM, Butler T, Ton B, Wilhelm K, Mitchell PB, Knight L, et al., 'Self-reported traumatic brain injury in a sample of impulsive violent offenders: neuropsychiatric correlates and possible "dose effects".', Front Psychol, 14 1243655 (2023) [C1]
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2023 |
Campagna MP, Xavier A, Stankovich J, Maltby VE, Slee M, Yeh WZ, et al., 'Parity is associated with long-term differences in DNA methylation at genes related to neural plasticity in multiple sclerosis', Clinical Epigenetics, 15 (2023) [C1]
Background: Pregnancy in women with multiple sclerosis (wwMS) is associated with a reduction of long-term disability progression. The mechanism that drives this effect is unknown,... [more]
Background: Pregnancy in women with multiple sclerosis (wwMS) is associated with a reduction of long-term disability progression. The mechanism that drives this effect is unknown, but converging evidence suggests a role for epigenetic mechanisms altering immune and/or central nervous system function. In this study, we aimed to identify whole blood and immune cell-specific DNA methylation patterns associated with parity in relapse-onset MS. Results: We investigated the association between whole blood and immune cell-type-specific genome-wide methylation patterns and parity in 192 women with relapse-onset MS, matched for age and disease severity. The median time from last pregnancy to blood collection was 16.7¿years (range = 1.5¿44.4¿years). We identified 2965 differentially methylated positions in whole blood, 68.5% of which were hypermethylated in parous women; together with two differentially methylated regions on Chromosomes 17 and 19 which mapped to TMC8 and ZNF577, respectively. Our findings validated 22 DMPs and 366 differentially methylated genes from existing literature on epigenetic changes associated with parity in wwMS. Differentially methylated genes in whole blood were enriched in neuronal structure and growth-related pathways. Immune cell-type-specific analysis using cell-type proportion estimates from statistical deconvolution of whole blood revealed further differential methylation in T cells specifically (four in CD4+ and eight in CD8+ T cells). We further identified reduced methylation age acceleration in parous women, demonstrating slower biological aging compared to nulligravida women. Conclusion: Differential methylation at genes related to neural plasticity offers a potential molecular mechanism driving the long-term effect of pregnancy on MS outcomes. Our results point to a potential ¿CNS signature¿ of methylation in peripheral immune cells, as previously described in relation to MS progression, induced by parity. As the first epigenome-wide association study of parity in wwMS reported, validation studies are needed to confirm our findings.
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2023 |
Møller P, Seppälä TT, Ahadova A, Crosbie EJ, Holinski-Feder E, Scott R, et al., 'Dominantly inherited micro-satellite instable cancer - the four Lynch syndromes - an EHTG, PLSD position statement.', Hered Cancer Clin Pract, 21 19 (2023) [C1]
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2023 |
Liu D, Meyer D, Fennessy B, Feng C, Cheng E, Johnson JS, et al., 'Schizophrenia risk conferred by rare protein-truncating variants is conserved across diverse human populations', Nature Genetics, 55 369-376 (2023) [C1]
Schizophrenia (SCZ) is a chronic mental illness and among the most debilitating conditions encountered in medical practice. A recent landmark SCZ study of the protein-coding regio... [more]
Schizophrenia (SCZ) is a chronic mental illness and among the most debilitating conditions encountered in medical practice. A recent landmark SCZ study of the protein-coding regions of the genome identified a causal role for ten genes and a concentration of rare variant signals in evolutionarily constrained genes1. This recent study¿and most other large-scale human genetics studies¿was mainly composed of individuals of European (EUR) ancestry, and the generalizability of the findings in non-EUR populations remains unclear. To address this gap, we designed a custom sequencing panel of 161 genes selected based on the current knowledge of SCZ genetics and sequenced a new cohort of 11,580 SCZ cases and 10,555 controls of diverse ancestries. Replicating earlier work, we found that cases carried a significantly higher burden of rare protein-truncating variants (PTVs) among evolutionarily constrained genes (odds ratio = 1.48; P = 5.4 × 10-6). In meta-analyses with existing datasets totaling up to 35,828 cases and 107,877 controls, this excess burden was largely consistent across five ancestral populations. Two genes (SRRM2 and AKAP11) were newly implicated as SCZ risk genes, and one gene (PCLO) was identified as shared by individuals with SCZ and those with autism. Overall, our results lend robust support to the rare allelic spectrum of the genetic architecture of SCZ being conserved across diverse human populations.
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2023 |
Maury EA, Sherman MA, Genovese G, Gilgenast TG, Kamath T, Burris SJ, et al., 'Schizophrenia-associated somatic copy-number variants from 12,834 cases reveal recurrent NRXN1 and ABCB11 disruptions', Cell Genomics, 3 (2023) [C1]
While germline copy-number variants (CNVs) contribute to schizophrenia (SCZ) risk, the contribution of somatic CNVs (sCNVs)¿present in some but not all cells¿remains unknown. We i... [more]
While germline copy-number variants (CNVs) contribute to schizophrenia (SCZ) risk, the contribution of somatic CNVs (sCNVs)¿present in some but not all cells¿remains unknown. We identified sCNVs using blood-derived genotype arrays from 12,834 SCZ cases and 11,648 controls, filtering sCNVs at loci recurrently mutated in clonal blood disorders. Likely early-developmental sCNVs were more common in cases (0.91%) than controls (0.51%, p = 2.68e-4), with recurrent somatic deletions of exons 1¿5 of the NRXN1 gene in five SCZ cases. Hi-C maps revealed ectopic, allele-specific loops forming between a potential cryptic promoter and non-coding cis-regulatory elements upon 5' deletions in NRXN1. We also observed recurrent intragenic deletions of ABCB11, encoding a transporter implicated in anti-psychotic response, in five treatment-resistant SCZ cases and showed that ABCB11 is specifically enriched in neurons forming mesocortical and mesolimbic dopaminergic projections. Our results indicate potential roles of sCNVs in SCZ risk.
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2023 |
Singh AK, Talseth-Palmer B, Xavier A, Scott RJ, Drabløs F, Sjursen W, 'Detection of germline variants with pathogenic potential in 48 patients with familial colorectal cancer by using whole exome sequencing.', BMC Med Genomics, 16 126 (2023) [C1]
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2023 |
Wiik MU, Negline M, Beisvåg V, Clapham M, Holliday E, Dueñas N, et al., 'MTHFR C677T and A1298C polymorphism's effect on risk of colorectal cancer in Lynch syndrome.', Sci Rep, 13 18783 (2023) [C1]
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2023 |
Xavier A, Maltby VE, Ewing E, Campagna MP, Burnard SM, Tegner JN, et al., 'DNA Methylation Signatures of Multiple Sclerosis Occur Independently of Known Genetic Risk and Are Primarily Attributed to B Cells and Monocytes', International Journal of Molecular Sciences, 24 12576-12576 [C1]
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2023 |
Hess JL, Quinn TP, Zhang C, Hearn GC, Chen S, Beveridge NJ, et al., 'BrainGENIE: The Brain Gene Expression and Network Imputation Engine', Translational Psychiatry, 13 (2023) [C1]
In vivo experimental analysis of human brain tissue poses substantial challenges and ethical concerns. To address this problem, we developed a computational method called the Brai... [more]
In vivo experimental analysis of human brain tissue poses substantial challenges and ethical concerns. To address this problem, we developed a computational method called the Brain Gene Expression and Network-Imputation Engine (BrainGENIE) that leverages peripheral-blood transcriptomes to predict brain tissue-specific gene-expression levels. Paired blood¿brain transcriptomic data collected by the Genotype-Tissue Expression (GTEx) Project was used to train BrainGENIE models to predict gene-expression levels in ten distinct brain regions using whole-blood gene-expression profiles. The performance of BrainGENIE was compared to PrediXcan, a popular method for imputing gene expression levels from genotypes. BrainGENIE significantly predicted brain tissue-specific expression levels for 2947¿11,816 genes (false-discovery rate-adjusted p < 0.05), including many transcripts that cannot be predicted significantly by a transcriptome-imputation method such as PrediXcan. BrainGENIE recapitulated measured diagnosis-related gene-expression changes in the brain for autism, bipolar disorder, and schizophrenia better than direct correlations from blood and predictions from PrediXcan. We developed a convenient software toolset for deploying BrainGENIE, and provide recommendations for how best to implement models. BrainGENIE complements and, in some ways, outperforms existing transcriptome-imputation tools, providing biologically meaningful predictions and opening new research avenues.
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2023 |
Bakker MK, Kanning JP, Abraham G, Martinsen AE, Winsvold BS, Zwart J-A, et al., 'Genetic Risk Score for Intracranial Aneurysms: Prediction of Subarachnoid Hemorrhage and Role in Clinical Heterogeneity', STROKE, 54 810-818 (2023) [C1]
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2023 |
Graham SE, Clarke SL, Wu K-HH, Kanoni S, Zajac GJM, Ramdas S, et al., 'The power of genetic diversity in genome-wide association studies of lipids (vol 600, pg 675, 2021)', NATURE, 618 E19-E20 (2023)
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2022 |
Bournazos AM, Riley LG, Bommireddipalli S, Ades L, Akesson LS, Al-Shinnag M, et al., 'Standardized practices for RNA diagnostics using clinically accessible specimens reclassifies 75% of putative splicing variants', Genetics in Medicine, 24 130-145 (2022) [C1]
Purpose: Genetic variants causing aberrant premessenger RNA splicing are increasingly being recognized as causal variants in genetic disorders. In this study, we devise standardiz... [more]
Purpose: Genetic variants causing aberrant premessenger RNA splicing are increasingly being recognized as causal variants in genetic disorders. In this study, we devise standardized practices for polymerase chain reaction (PCR)-based RNA diagnostics using clinically accessible specimens (blood, fibroblasts, urothelia, biopsy). Methods: A total of 74 families with diverse monogenic conditions (31% prenatal-congenital onset, 47% early childhood, and 22% teenage-adult onset) were triaged into PCR-based RNA testing, with comparative RNA sequencing for 19 cases. Results: Informative RNA assay data were obtained for 96% of cases, enabling variant reclassification for 75% variants that can be used for genetic counseling (71%), to inform clinical care (32%) and prenatal counseling (41%). Variant-associated mis-splicing was highly reproducible for 28 cases with samples from =2 affected individuals or heterozygotes and 10 cases with =2 biospecimens. PCR amplicons encompassing another segregated heterozygous variant was vital for clinical interpretation of 22 of 79 variants to phase RNA splicing events and discern complete from partial mis-splicing. Conclusion: RNA diagnostics enabled provision of a genetic diagnosis for 64% of recruited cases. PCR-based RNA diagnostics has capacity to analyze 81.3% of clinically significant genes, with long amplicons providing an advantage over RNA sequencing to phase RNA splicing events. The Australasian Consortium for RNA Diagnostics (SpliceACORD) provide clinically-endorsed, standardized protocols and recommendations for interpreting RNA assay data.
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2022 |
Pardinas AF, Smart SE, Willcocks IR, Holmans PA, Dennison CA, Lynham AJ, et al., 'Interaction Testing and Polygenic Risk Scoring to Estimate the Association of Common Genetic Variants With Treatment Resistance in Schizophrenia', JAMA PSYCHIATRY, 79 260-269 (2022) [C1]
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2022 |
Lim BWX, Li N, Rowley SM, Thompson ER, McInerny S, Zethoven M, et al., 'Integration of tumour sequencing and case-control data to assess pathogenicity of
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2022 |
Okbay A, Wu Y, Wang N, Jayashankar H, Bennett M, Nehzati SM, et al., 'Polygenic prediction of educational attainment within and between families from genome-wide association analyses in 3 million individuals', Nature Genetics, 54 437-449 (2022) [C1]
We conduct a genome-wide association study (GWAS) of educational attainment (EA) in a sample of ~3 million individuals and identify 3,952 approximately uncorrelated genome-wide-si... [more]
We conduct a genome-wide association study (GWAS) of educational attainment (EA) in a sample of ~3 million individuals and identify 3,952 approximately uncorrelated genome-wide-significant single-nucleotide polymorphisms (SNPs). A genome-wide polygenic predictor, or polygenic index (PGI), explains 12¿16% of EA variance and contributes to risk prediction for ten diseases. Direct effects (i.e., controlling for parental PGIs) explain roughly half the PGI¿s magnitude of association with EA and other phenotypes. The correlation between mate-pair PGIs is far too large to be consistent with phenotypic assortment alone, implying additional assortment on PGI-associated factors. In an additional GWAS of dominance deviations from the additive model, we identify no genome-wide-significant SNPs, and a separate X-chromosome additive GWAS identifies 57.
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2022 |
Ahearn TU, Zhang H, Michailidou K, Milne RL, Bolla MK, Dennis J, et al., 'Common variants in breast cancer risk loci predispose to distinct tumor subtypes', Breast Cancer Research, 24 (2022) [C1]
Background: Genome-wide association studies (GWAS) have identified multiple common breast cancer susceptibility variants. Many of these variants have differential associations by ... [more]
Background: Genome-wide association studies (GWAS) have identified multiple common breast cancer susceptibility variants. Many of these variants have differential associations by estrogen receptor (ER) status, but how these variants relate with other tumor features and intrinsic molecular subtypes is unclear. Methods: Among 106,571 invasive breast cancer cases and 95,762 controls of European ancestry with data on 173 breast cancer variants identified in previous GWAS, we used novel two-stage polytomous logistic regression models to evaluate variants in relation to multiple tumor features (ER, progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and grade) adjusting for each other, and to intrinsic-like subtypes. Results: Eighty-five of 173 variants were associated with at least one tumor feature (false discovery rate < 5%), most commonly ER and grade, followed by PR and HER2. Models for intrinsic-like subtypes found nearly all of these variants (83 of 85) associated at p < 0.05 with risk for at least one luminal-like subtype, and approximately half (41 of 85) of the variants were associated with risk of at least one non-luminal subtype, including 32 variants associated with triple-negative (TN) disease. Ten variants were associated with risk of all subtypes in different magnitude. Five variants were associated with risk of luminal A-like and TN subtypes in opposite directions. Conclusion: This report demonstrates a high level of complexity in the etiology heterogeneity of breast cancer susceptibility variants and can inform investigations of subtype-specific risk prediction.
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2022 |
Ip E, McNeil C, Grimison P, Scheinberg T, Tudini E, Ho G, et al., 'Catastrophic chemotherapy toxicity leading to diagnosis of Fanconi anaemia due to
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2022 |
Mullins N, Kang J, Campos A, Coleman JR, Edwards AC, Galfalvy H, et al., 'Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors', BIOLOGICAL PSYCHIATRY, 91 313-327 (2022) [C1]
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2022 |
Campagna MP, Xavier A, Lea RA, Stankovich J, Maltby VE, Butzkueven H, et al., 'Whole-blood methylation signatures are associated with and accurately classify multiple sclerosis disease severity', Clinical Epigenetics, 14 (2022) [C1]
Background: The variation in multiple sclerosis (MS) disease severity is incompletely explained by genetics, suggesting genetic and environmental interactions are involved. Moreov... [more]
Background: The variation in multiple sclerosis (MS) disease severity is incompletely explained by genetics, suggesting genetic and environmental interactions are involved. Moreover, the lack of prognostic biomarkers makes it difficult for clinicians to optimise care. DNA methylation is one epigenetic mechanism by which gene¿environment interactions can be assessed. Here, we aimed to identify DNA methylation patterns associated with mild and severe relapse-onset MS (RMS) and to test the utility of methylation as a predictive biomarker. Methods: We conducted an epigenome-wide association study between 235 females with mild (n = 119) or severe (n = 116) with RMS. Methylation was measured with the Illumina methylationEPIC array and analysed using logistic regression. To generate hypotheses about the functional consequence of differential methylation, we conducted gene set enrichment analysis using ToppGene. We compared the accuracy of three machine learning models in classifying disease severity: (1) clinical data available at baseline (age at onset and first symptoms) built using elastic net (EN) regression, (2) methylation data using EN regression and (3) a weighted methylation risk score of differentially methylated positions (DMPs) from the main analysis using logistic regression. We used a conservative 70:30 test:train split for classification modelling. A false discovery rate threshold of 0.05 was used to assess statistical significance. Results: Females with mild or severe RMS had 1472 DMPs in whole blood (839 hypermethylated, 633 hypomethylated in the severe group). Differential methylation was enriched in genes related to neuronal cellular compartments and processes, and B-cell receptor signalling. Whole-blood methylation levels at 1708 correlated CpG sites classified disease severity more accurately (machine learning model 2, AUC = 0.91) than clinical data (model 1, AUC = 0.74) or the wMRS (model 3, AUC = 0.77). Of the 1708 selected CpGs, 100 overlapped with DMPs from the main analysis at the gene level. These overlapping genes were enriched in neuron projection and dendrite extension, lending support to our finding that neuronal processes, rather than immune processes, are implicated in disease severity. Conclusion: RMS disease severity is associated with whole-blood methylation at genes related to neuronal structure and function. Moreover, correlated whole-blood methylation patterns can assign disease severity in females with RMS more accurately than clinical data available at diagnosis.
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2022 |
Trubetskoy V, Pardiñas AF, Qi T, Panagiotaropoulou G, Awasthi S, Bigdeli TB, et al., 'Mapping genomic loci implicates genes and synaptic biology in schizophrenia', Nature, 604 502-508 (2022) [C1]
Schizophrenia has a heritability of 60¿80%1, much of which is attributable to common risk alleles. Here, in a two-stage genome-wide association study of up to 76,755 individuals w... [more]
Schizophrenia has a heritability of 60¿80%1, much of which is attributable to common risk alleles. Here, in a two-stage genome-wide association study of up to 76,755 individuals with schizophrenia and 243,649 control individuals, we report common variant associations at 287 distinct genomic loci. Associations were concentrated in genes that are expressed in excitatory and inhibitory neurons of the central nervous system, but not in other tissues or cell types. Using fine-mapping and functional genomic data, we identify 120 genes (106 protein-coding) that are likely to underpin associations at some of these loci, including 16 genes with credible causal non-synonymous or untranslated region variation. We also implicate fundamental processes related to neuronal function, including synaptic organization, differentiation and transmission. Fine-mapped candidates were enriched for genes associated with rare disruptive coding variants in people with schizophrenia, including the glutamate receptor subunit GRIN2A and transcription factor SP4, and were also enriched for genes implicated by such variants in neurodevelopmental disorders. We identify biological processes relevant to schizophrenia pathophysiology; show convergence of common and rare variant associations in schizophrenia and neurodevelopmental disorders; and provide a resource of prioritized genes and variants to advance mechanistic studies.
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2022 |
Patel Y, Shin J, Abe C, Agartz I, Alloza C, Alnaes D, et al., 'Virtual Ontogeny of Cortical Growth Preceding Mental Illness', BIOLOGICAL PSYCHIATRY, 92 299-313 (2022) [C1]
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2022 |
White C, Scott RJ, Paul C, Ziolkowski A, Mossman D, Fox SB, et al., 'Dihydropyrimidine Dehydrogenase Deficiency and Implementation of Upfront
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2022 |
Moller P, Seppala T, Dowty JG, Haupt S, Dominguez-Valentin M, Sunde L, et al., 'Colorectal cancer incidences in Lynch syndrome: a comparison of results from the prospective lynch syndrome database and the international mismatch repair consortium', HEREDITARY CANCER IN CLINICAL PRACTICE, 20 (2022) [C1]
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2022 |
Zlowocka-Perlowska E, van de Wetering T, Toloczko-Grabarek A, Scott RJ, Lubinski J, 'Bladder cancer survival in patients with NOD2 or CDKN2A variants', Oncotarget, 13 628-640 (2022) [C1]
Purpose: The association between the NOD2 c.3020insC allele and CDKN2A missense variant c.442G>A (p.P.A148T) and survival of patients with bladder or kidney cancer remains cont... [more]
Purpose: The association between the NOD2 c.3020insC allele and CDKN2A missense variant c.442G>A (p.P.A148T) and survival of patients with bladder or kidney cancer remains controversial. Materials and Methods: We compared the allele frequencies of NOD2 c.3020insC and CDKN2A p.A148T allele in 706 patients with bladder cancer, 410 cases with kidney cancer against two control groups. The Cox proportional hazards model was used to determine whether there were any survival differences between carriers of the NOD2 c.3020insC or the CDKN2A p.A148T variant. Results: Among the three patient subgroups: patients under 60 years of age, non-smokers and a third with histological features of low grade noninvasive papillary bladder cancer, we observed that the c.3020insC allele had a nominal statistically significant effect on survival. We also observed that the NOD2 c.3020insC variant was more frequent in patients with bladder cancer aged between 51 and 60 years. There was some nominal evidence that the CDKN2A p.A148T polymorphism reduced survival in the subgroup of bladder cancer patients under 60 years of age. We observed that in kidney cancer patients, the incidence of the NOD2 variant appeared to be lower in the group aged between 60 and 70 years, however, this was not statistically significant. In addition, in patients with histological features of grade III chromophobic kidney cancer, the c.3020insC allele also appeared to be overrepresented but this too was not statistically significant. Conclusion: We have shown that the NOD2 c.3020insC allele and the CDKN2A p.A148T polymorphism does not play a role in the survival of patients with bladder cancer.
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2022 |
Burnard SM, Lea RA, Benton M, Eccles D, Kennedy DW, Lechner-Scott J, Scott RJ, 'Capturing SNP Association across the NK Receptor and HLA Gene Regions in Multiple Sclerosis by Targeted Penalised Regression Models', Genes, 13 (2022) [C1]
Conventional genome-wide association studies (GWASs) of complex traits, such as Multiple Sclerosis (MS), are reliant on per-SNP p-values and are therefore heavily burdened by mult... [more]
Conventional genome-wide association studies (GWASs) of complex traits, such as Multiple Sclerosis (MS), are reliant on per-SNP p-values and are therefore heavily burdened by multiple testing correction. Thus, in order to detect more subtle alterations, ever increasing sample sizes are required, while ignoring potentially valuable information that is readily available in existing datasets. To overcome this, we used penalised regression incorporating elastic net with a stability selection method by iterative subsampling to detect the potential interaction of loci with MS risk. Through re-analysis of the ANZgene dataset (1617 cases and 1988 controls) and an IMSGC dataset as a replication cohort (1313 cases and 1458 controls), we identified new association signals for MS predisposition, including SNPs above and below conventional significance thresholds while targeting two natural killer receptor loci and the well-established HLA loci. For example, rs2844482 (98.1% iterations), otherwise ignored by conventional statistics (p = 0.673) in the same dataset, was independently strongly associated with MS in another GWAS that required more than 40 times the number of cases (~45 K). Further comparison of our hits to those present in a large-scale meta-analysis, confirmed that the majority of SNPs identified by the elastic net model reached conventional statistical GWAS thresholds (p < 5 × 10-8 ) in this much larger dataset. Moreover, we found that gene variants involved in oxidative stress, in addition to innate immunity, were associated with MS. Overall, this study highlights the benefit of using more advanced statistical methods to (re-)analyse subtle genetic variation among loci that have a biological basis for their contribution to disease risk.
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2022 |
Scott RJ, 'Modifier genes and Lynch syndrome: some considerations', HEREDITARY CANCER IN CLINICAL PRACTICE, 20 (2022) [C1]
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2022 |
Blokland GAM, Grove J, Chen C-Y, Cotsapas C, Tobet S, Handa R, et al., 'Sex-Dependent Shared and Nonshared Genetic Architecture Across Mood and Psychotic Disorders.', Biol Psychiatry, 91 102-117 (2022) [C1]
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2022 |
Mathers JC, Elliott F, Macrae F, Mecklin JP, Möslein G, McRonald FE, et al., 'Cancer Prevention with Resistant Starch in Lynch Syndrome Patients in the CAPP2-Randomized Placebo Controlled Trial: Planned 10-Year Follow-up', Cancer Prevention Research, 15 623-634 (2022) [C1]
The CAPP2 trial investigated the long-term effects of aspirin and resistant starch on cancer incidence in patients with Lynch syndrome (LS). Participants with LS were randomized d... [more]
The CAPP2 trial investigated the long-term effects of aspirin and resistant starch on cancer incidence in patients with Lynch syndrome (LS). Participants with LS were randomized double-blind to 30 g resistant starch (RS) daily or placebo for up to 4 years. We present long-term cancer outcomes based on the planned 10-year follow-up from recruitment, supplemented by National Cancer Registry data to 20 years in England, Wales, and Finland. Overall, 463 participants received RS and 455 participants received placebo. After up to 20 years follow-up, there was no difference in colorectal cancer incidence (n = 52 diagnosed with colorectal cancer among those randomized to RS against n = 53 on placebo) but fewer participants had non-colorectal LS cancers in those randomized to RS (n = 27) compared with placebo (n = 48); intention-to-treat (ITT) analysis [HR, 0.54; 95% confidence interval (CI), 0.33-0.86; P = 0.010]. In ITT analysis, allowing for multiple primary cancer diagnoses among participants by calculating incidence rate ratios (IRR) confirmed the protective effect of RS against non-colorectal cancer LS cancers (IRR, 0.52; 95% CI, 0.32-0.84; P = 0.0075). These effects are particularly pronounced for cancers of the upper GI tract; 5 diagnoses in those on RS versus 21 diagnoses on placebo. The reduction in non-colorectal cancer LS cancers was detectable in the first 10 years and continued in the next decade. For colorectal cancer, ITT analysis showed no effect of RS on colorectal cancer risk (HR, 0.92; 95% CI, 0.62-1.34; P = 0.63). There was no interaction between aspirin and RS treatments. In conclusion, 30 g daily RS appears to have a substantial protective effect against non-colorectal cancer cancers for patients with LS. Prevention Relevance: Regular bowel screening and aspirin reduce colorectal cancer among patients with LS but extracolonic cancers are difficult to detect and manage. This study suggests that RS reduces morbidity associated with extracolonic cancers.
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2022 |
Wong-Brown M, McPhillips M, Gleeson M, Spigelman AD, Meldrum CJ, Dooley S, Scott RJ, 'When is a mutation not a mutation: the case of the c.594-2A \ C splice variant in a woman harbouring another BRCA1 mutation in trans (vol 14, 6, 2016)', HEREDITARY CANCER IN CLINICAL PRACTICE, 20 (2022)
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2022 |
Ramdas S, Judd J, Graham SE, Kanoni S, Wang Y, Surakka I, et al., 'A multi-layer functional genomic analysis to understand noncoding genetic variation in lipids', AMERICAN JOURNAL OF HUMAN GENETICS, 109 1366-1387 (2022) [C1]
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2022 |
Yengo L, Vedantam S, Marouli E, Sidorenko J, Bartell E, Sakaue S, et al., 'A saturated map of common genetic variants associated with human height', NATURE, 610 704-+ (2022) [C1]
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2022 |
Kanoni S, Graham SE, Wang Y, Surakka I, Ramdas S, Zhu X, et al., 'Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis', GENOME BIOLOGY, 23 (2022) [C1]
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2022 |
Gaddis N, Mathur R, Marks J, Zhou L, Quach B, Waldrop A, et al., 'Multi-trait genome-wide association study of opioid addiction: OPRM1 and beyond', SCIENTIFIC REPORTS, 12 (2022) [C1]
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2022 |
Lahti J, Tuominen S, Yang Q, Pergola G, Ahmad S, Amin N, et al., 'Genome-wide meta-analyses reveal novel loci for verbal short-term memory and learning', Molecular Psychiatry, 27 4419-4431 (2022) [C1]
Understanding the genomic basis of memory processes may help in combating neurodegenerative disorders. Hence, we examined the associations of common genetic variants with verbal s... [more]
Understanding the genomic basis of memory processes may help in combating neurodegenerative disorders. Hence, we examined the associations of common genetic variants with verbal short-term memory and verbal learning in adults without dementia or stroke (N = 53,637). We identified novel loci in the intronic region of CDH18, and at 13q21 and 3p21.1, as well as an expected signal in the APOE/APOC1/TOMM40 region. These results replicated in an independent sample. Functional and bioinformatic analyses supported many of these loci and further implicated POC1. We showed that polygenic score for verbal learning associated with brain activation in right parieto-occipital region during working memory task. Finally, we showed genetic correlations of these memory traits with several neurocognitive and health outcomes. Our findings suggest a role of several genomic loci in verbal memory processes.
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2022 |
Pariyar M, Thorne RF, Scott RJ, Avery-Kiejda KA, 'Verification and Validation of a Four-Gene Panel as a Prognostic Indicator in Triple Negative Breast Cancer', Frontiers in Oncology, 12 (2022) [C1]
Triple negative breast cancer (TNBC) is a highly aggressive subtype with a high rate of metastasis, early distant recurrence and resistance to therapy leading to worse survival th... [more]
Triple negative breast cancer (TNBC) is a highly aggressive subtype with a high rate of metastasis, early distant recurrence and resistance to therapy leading to worse survival than other breast cancer subtypes. There are no well-established biomarkers that can determine women who will do better and those who are likely to have poorer outcomes with TNBC, nor are there targeted therapies. Thus, the identification of prognostic and/or predictive biomarkers will enable tailored therapies based on their likelihood of disease outcomes and may prevent over- and under-diagnosis. Previous studies from our laboratory have identified four genes (ANP32E, DSC2, ANKRD30A and IL6ST/gp130) that are specific to TNBC and were associated with lymph node metastasis (LNmets), the earliest indicator of tumor progression via distal spread. This study aimed to validate these findings using absolute quantitation by digital droplet PCR (ddPCR) and to determine relationships with clinicopathological features and survival. Our analysis confirmed all four genes displayed significant expression differences between TNBC cases and non-TNBC cases. Moreover, low IL6ST expression was significantly associated with grade 3 disease, hormone receptor negativity and earlier age at diagnosis; low ANKRD30A expression was associated with tumor size; and high ANP32E expression was significantly associated with grade and the number of positive lymph nodes. Individually, three of the four genes were associated with relapse-free survival in TNBC and in combination, all four genes were significantly associated with TNBC survival, but not in hormone receptor-positive cases. Collectively our results suggest that the four genes may have utility in TNBC prognostication.
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2022 |
White C, Scott R, Paul CL, Ackland SP, 'Pharmacogenomics in the era of personalised medicine', MEDICAL JOURNAL OF AUSTRALIA, 217 510-513 (2022)
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2022 |
Dennis J, Tyrer JP, Walker LC, Michailidou K, Dorling L, Bolla MK, et al., 'Rare germline copy number variants (CNVs) and breast cancer risk', Communications Biology, 5 (2022) [C1]
Germline copy number variants (CNVs) are pervasive in the human genome but potential disease associations with rare CNVs have not been comprehensively assessed in large datasets. ... [more]
Germline copy number variants (CNVs) are pervasive in the human genome but potential disease associations with rare CNVs have not been comprehensively assessed in large datasets. We analysed rare CNVs in genes and non-coding regions for 86,788 breast cancer cases and 76,122 controls of European ancestry with genome-wide array data. Gene burden tests detected the strongest association for deletions in BRCA1 (P = 3.7E-18). Nine other genes were associated with a p-value < 0.01 including known susceptibility genes CHEK2 (P = 0.0008), ATM (P = 0.002) and BRCA2 (P = 0.008). Outside the known genes we detected associations with p-values < 0.001 for either overall or subtype-specific breast cancer at nine deletion regions and four duplication regions. Three of the deletion regions were in established common susceptibility loci. To the best of our knowledge, this is the first genome-wide analysis of rare CNVs in a large breast cancer case-control dataset. We detected associations with exonic deletions in established breast cancer susceptibility genes. We also detected suggestive associations with non-coding CNVs in known and novel loci with large effects sizes. Larger sample sizes will be required to reach robust levels of statistical significance.
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2021 |
Johnson N, Maguire S, Morra A, Kapoor PM, Tomczyk K, Jones ME, et al., 'CYP3A7*1C allele: linking premenopausal oestrone and progesterone levels with risk of hormone receptor-positive breast cancers', British Journal of Cancer, 124 842-854 (2021) [C1]
Background: Epidemiological studies provide strong evidence for a role of endogenous sex hormones in the aetiology of breast cancer. The aim of this analysis was to identify genet... [more]
Background: Epidemiological studies provide strong evidence for a role of endogenous sex hormones in the aetiology of breast cancer. The aim of this analysis was to identify genetic variants that are associated with urinary sex-hormone levels and breast cancer risk. Methods: We carried out a genome-wide association study of urinary oestrone-3-glucuronide and pregnanediol-3-glucuronide levels in 560 premenopausal women, with additional analysis of progesterone levels in 298 premenopausal women. To test for the association with breast cancer risk, we carried out follow-up genotyping in 90,916 cases and 89,893 controls from the Breast Cancer Association Consortium. All women were of European ancestry. Results: For pregnanediol-3-glucuronide, there were no genome-wide significant associations; for oestrone-3-glucuronide, we identified a single peak mapping to the CYP3A locus, annotated by rs45446698. The minor rs45446698-C allele was associated with lower oestrone-3-glucuronide (-49.2%, 95% CI -56.1% to -41.1%, P = 3.1 × 10¿18); in follow-up analyses, rs45446698-C was also associated with lower progesterone (-26.7%, 95% CI -39.4% to -11.6%, P = 0.001) and reduced risk of oestrogen and progesterone receptor-positive breast cancer (OR = 0.86, 95% CI 0.82¿0.91, P = 6.9 × 10¿8). Conclusions: The CYP3A7*1C allele is associated with reduced risk of hormone receptor-positive breast cancer possibly mediated via an effect on the metabolism of endogenous sex hormones in premenopausal women.
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2021 |
Hess JL, Tylee DS, Mattheisen M, Børglum AD, Als TD, Grove J, et al., 'A polygenic resilience score moderates the genetic risk for schizophrenia', Molecular Psychiatry, 26 800-815 (2021) [C1]
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2021 |
Kho P-F, Amant F, Annibali D, Ashton K, Attia J, Auer PL, et al., 'Mendelian randomization analyses suggest a role for cholesterol in the development of endometrial cancer', INTERNATIONAL JOURNAL OF CANCER, 148 307-319 (2021) [C1]
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2021 |
Lener MR, Reszka E, Marciniak W, Lesicka M, Baszuk P, Jablonska E, et al., 'Blood cadmium levels as a marker for early lung cancer detection', Journal of Trace Elements in Medicine and Biology, 64 (2021) [C1]
Background: We assessed whether blood cadmium levels were associated with incident lung cancer and could be used in the context of a screening program for early-stage lung cancer.... [more]
Background: We assessed whether blood cadmium levels were associated with incident lung cancer and could be used in the context of a screening program for early-stage lung cancer. Material and methods: We measured blood cadmium levels among 205 lung cancer patients and 205 matched controls. Cases and controls were matched for sex, age and smoking history (total pack-years, years since cessation for former smokers). Results: The odds ratio for those in the highest quartile of cadmium level (versus lowest) was four-fold (OR = 4.41, 95 % CI:2.01¿9.67, p < 0.01). The association was present in former smokers (OR = 16.8, 95 % CI:3.96-71.2, p < 0.01), but not in current smokers (OR = 1.23, 95 % CI: 0.34¿4.38) or in never smokers (OR not defined). Among former smokers, the association was present in both early- and late-stage lung cancer. Conclusion: Blood cadmium levels may be a marker to help with the early detection of lung cancer among former smokers.
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2021 |
Glubb DM, Thompson DJ, Aben KKH, Alsulimani A, Amant F, Annibali D, et al., 'Cross-Cancer Genome-Wide Association Study of Endometrial Cancer and Epithelial Ovarian Cancer Identifies Genetic Risk Regions Associated with Risk of Both Cancers', CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION, 30 217-228 (2021) [C1]
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2021 |
Ni G, Zeng J, Revez JA, Wang Y, Zheng Z, Ge T, et al., 'A Comparison of Ten Polygenic Score Methods for Psychiatric Disorders Applied Across Multiple Cohorts', BIOLOGICAL PSYCHIATRY, 90 611-620 (2021) [C1]
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2021 |
Pietrzak S, Wojcik J, Baszuk P, Marciniak W, Wojtys M, Debniak T, et al., 'Influence of the Levels of Arsenic, Cadmium, Mercury and Lead on Overall Survival in Lung Cancer', BIOMOLECULES, 11 (2021) [C1]
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2021 |
Scott RJ, Mehta A, Macedo GS, Borisov PS, Kanesvaran R, El Metnawy W, 'Genetic testing for homologous recombination repair (HRR) in metastatic castration-resistant prostate cancer (mCRPC): challenges and solutions', Oncotarget, 12 1600-1614 (2021) [C1]
Patients with metastatic castration-resistant prostate cancer (mCRPC) have an average survival of only 13 months. Identification of novel predictive and actionable biomarkers in t... [more]
Patients with metastatic castration-resistant prostate cancer (mCRPC) have an average survival of only 13 months. Identification of novel predictive and actionable biomarkers in the homologous recombination repair (HRR) pathway in up to a quarter of patients with mCRPC has led to the approval of targeted therapies like poly-ADP ribose polymerase inhibitors (PARPi), with the potential to improve survival outcomes. The approval of PARPi has led to guideline bodies such as the National Comprehensive Cancer Network (NCCN) to actively recommend germline and or somatic HRR gene panel testing to identify patients who will benefit from PARPi. However, there are several challenges as genetic testing is still at an early stage especially in low- and middle-income countries, with cost and availability being major impediments. In addition, there are issues such as choice of optimal tissue for genetic testing, archival, storage, retrieval of tissue blocks, interpretation and classification of variants in the HRR pathway, and the need for pretest and post-test genetic counseling. This review provides insights into the HRR gene mutations prevalent in mCRPC and the challenges for a more widespread gene testing to identify actionable germline pathogenic variants and somatic mutations in the HRR pathway, and proposes a clinical algorithm to enhance the efficiency of the gene testing process.
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2021 |
Skerrett-Byrne DA, Bromfield EG, Murray HC, Jamaluddin MFB, Jarnicki AG, Fricker M, et al., 'Time-resolved proteomic profiling of cigarette smoke-induced experimental chronic obstructive pulmonary disease', Respirology, 26 960-973 (2021) [C1]
Background and objective: Chronic obstructive pulmonary disease (COPD) is the third leading cause of illness and death worldwide. Current treatments aim to control symptoms with n... [more]
Background and objective: Chronic obstructive pulmonary disease (COPD) is the third leading cause of illness and death worldwide. Current treatments aim to control symptoms with none able to reverse disease or stop its progression. We explored the major molecular changes in COPD pathogenesis. Methods: We employed quantitative label-based proteomics to map the changes in the lung tissue proteome of cigarette smoke-induced experimental COPD that is induced over 8 weeks and progresses over 12 weeks. Results: Quantification of 7324 proteins enabled the tracking of changes to the proteome. Alterations in protein expression profiles occurred in the induction phase, with 18 and 16 protein changes at 4- and 6-week time points, compared to age-matched controls, respectively. Strikingly, 269 proteins had altered expression after 8 weeks when the hallmark pathological features of human COPD emerge, but this dropped to 27 changes at 12 weeks with disease progression. Differentially expressed proteins were validated using other mouse and human COPD bronchial biopsy samples. Major changes in RNA biosynthesis (heterogeneous nuclear ribonucleoproteins C1/C2 [HNRNPC] and RNA-binding protein Musashi homologue 2 [MSI2]) and modulators of inflammatory responses (S100A1) were notable. Mitochondrial dysfunction and changes in oxidative stress proteins also occurred. Conclusion: We provide a detailed proteomic profile, identifying proteins associated with the pathogenesis and disease progression of COPD establishing a platform to develop effective new treatment strategies.
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2021 |
Coignard J, Lush M, Beesley J, O'Mara TA, Dennis J, Tyrer JP, et al., 'Author Correction: A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers.', Nature communications, 12 2986 (2021)
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2021 |
Kapoor PM, Mavaddat N, Choudhury PP, Wilcox AN, Lindström S, Behrens S, et al., 'Combined Associations of a Polygenic Risk Score and Classical Risk Factors with Breast Cancer Risk', Journal of the National Cancer Institute, 113 329-337 (2021) [C1]
We evaluated the joint associations between a new 313-variant PRS (PRS313) and questionnaire-based breast cancer risk factors for women of European ancestry, using 72 284 cases an... [more]
We evaluated the joint associations between a new 313-variant PRS (PRS313) and questionnaire-based breast cancer risk factors for women of European ancestry, using 72 284 cases and 80 354 controls from the Breast Cancer Association Consortium. Interactions were evaluated using standard logistic regression and a newly developed case-only method for breast cancer risk overall and by estrogen receptor status. After accounting for multiple testing, we did not find evidence that per-standard deviation PRS313 odds ratio differed across strata defined by individual risk factors. Goodness-of-fit tests did not reject the assumption of a multiplicative model between PRS313 and each risk factor. Variation in projected absolute lifetime risk of breast cancer associated with classical risk factors was greater for women with higher genetic risk (PRS313 and family history) and, on average, 17.5% higher in the highest vs lowest deciles of genetic risk. These findings have implications for risk prevention for women at increased risk of breast cancer.
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2021 |
Park HA, Neumeyer S, Michailidou K, Bolla MK, Wang Q, Dennis J, et al., 'Mendelian randomisation study of smoking exposure in relation to breast cancer risk', British Journal of Cancer, 125 1135-1145 (2021) [C1]
Background: Despite a modest association between tobacco smoking and breast cancer risk reported by recent epidemiological studies, it is still equivocal whether smoking is causal... [more]
Background: Despite a modest association between tobacco smoking and breast cancer risk reported by recent epidemiological studies, it is still equivocal whether smoking is causally related to breast cancer risk. Methods: We applied Mendelian randomisation (MR) to evaluate a potential causal effect of cigarette smoking on breast cancer risk. Both individual-level data as well as summary statistics for 164 single-nucleotide polymorphisms (SNPs) reported in genome-wide association studies of lifetime smoking index (LSI) or cigarette per day (CPD) were used to obtain MR effect estimates. Data from 108,420 invasive breast cancer cases and 87,681 controls were used for the LSI analysis and for the CPD analysis conducted among ever-smokers from 26,147 cancer cases and 26,072 controls. Sensitivity analyses were conducted to address pleiotropy. Results: Genetically predicted LSI was associated with increased breast cancer risk (OR 1.18 per SD, 95% CI: 1.07¿1.30, P = 0.11 × 10¿2), but there was no evidence of association for genetically predicted CPD (OR 1.02, 95% CI: 0.78¿1.19, P = 0.85). The sensitivity analyses yielded similar results and showed no strong evidence of pleiotropic effect. Conclusion: Our MR study provides supportive evidence for a potential causal association with breast cancer risk for lifetime smoking exposure but not cigarettes per day among smokers.
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2021 |
Bancroft EK, Page EC, Brook MN, Thomas S, Taylor N, Pope J, et al., 'A prospective prostate cancer screening programme for men with pathogenic variants in mismatch repair genes (IMPACT): initial results from an international prospective study', LANCET ONCOLOGY, 22 1618-1631 (2021) [C1]
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2021 |
Ahadova A, Seppälä TT, Engel C, Gallon R, Burn J, Holinski-Feder E, et al., 'The unnatural history of colorectal cancer in Lynch syndrome: Lessons from colonoscopy surveillance', International Journal of Cancer, 148 800-811 (2021) [C1]
Individuals with Lynch syndrome (LS), one of the most common inherited cancer syndromes, are at increased risk of developing malignancies, in particular colorectal cancer (CRC). R... [more]
Individuals with Lynch syndrome (LS), one of the most common inherited cancer syndromes, are at increased risk of developing malignancies, in particular colorectal cancer (CRC). Regular colonoscopy with polypectomy is recommended to reduce CRC risk in LS individuals. However, recent independent studies demonstrated that a substantial proportion of LS individuals develop CRC despite regular colonoscopy. The reasons for this surprising observation confirmed by large prospective studies are a matter of debate. In this review, we collect existing evidence from clinical, epidemiological and molecular studies and interpret them with regard to the origins and progression of LS-associated CRC. Alongside with hypotheses addressing colonoscopy quality and pace of progression from adenoma to cancer, we discuss the role of alternative precursors and immune system in LS-associated CRC. We also identify gaps in current knowledge and make suggestions for future studies aiming at improved CRC prevention for LS individuals.
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Nova |
2021 |
Ngo TTD, Lea RA, Maksemous N, Eccles DA, Smith RA, Dunn PJ, et al., 'The MinION as a cost-effective technology for diagnostic screening of the SCN1A gene in epilepsy patients', Epilepsy Research, 172 (2021) [C1]
The MinION is a portable DNA sequencer that allows real time sequencing at low capital cost investment. We assessed accuracy and cost-effectivess of the MinION for genetic diagnos... [more]
The MinION is a portable DNA sequencer that allows real time sequencing at low capital cost investment. We assessed accuracy and cost-effectivess of the MinION for genetic diagnostic testing of known SCN1A mutations that cause Dravet Syndrome (DS). DNA samples (n = 7) from DS patients previously shown to carry SCN1A mutations via Ion Torrent and Sanger sequencing were sequenced using the MinION. SCN1A amplicons for 8 exons were sequenced using the MinION with 1D chemistry on an R9.4 flow cell. All known missense mutations were detected in all samples showing 100 % concordance with results from other methods. However, the MinION failed to detect the insertions/deletions (INDELs) present in these patients. Nevertheless, these results indicate that MinION is a cost-effective platform for use as an initial screening step in the detection of nucleotide substitution mutations in in SCN1A, especially in under-resourced laboratories or hospitals. Further improvements are required to reliably detect INDELS in this gene.
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2021 |
Rogoza-Janiszewska E, Malinska K, Górski B, Scott RJ, Cybulski C, Kluzniak W, et al., 'Prevalence of germline TP53 variants among early-onset breast cancer patients from Polish population', Breast Cancer, 28 226-235 (2021) [C1]
Background: The objective of this study was to determine spectrum and prevalence of germline mutations in TP53 gene among Polish women with early-onset breast cancer (BC), which h... [more]
Background: The objective of this study was to determine spectrum and prevalence of germline mutations in TP53 gene among Polish women with early-onset breast cancer (BC), which has not been determined until now. Methods: A cohort of 100 females with BC diagnosed = 30¿years of age and with a positive family history of cancer was used as a discovery cohort. 1880 women with BC = 45¿years old and a control group of 2000 healthy women were genotyped as a replication phase of this study. Results: Four heterozygous pathogenic missense mutations were detected in a group of 100 patients with early-onset breast cancer. On the basis of software prediction and available literature data, all these variants were defined as pathogenic. None of these TP53 variants were detected among 1880 breast cancer patients and 2000 healthy controls. No large mutations were found among early-onset cases using MLPA reaction. Conclusion: Germline pathogenic TP53 variants were found in 4% early-onset Polish BC patients. No founder mutations were identified in Polish population. To improve the treatment and surveillance screening, the search for germline TP53 pathogenic variants is recommended for all female BC cases diagnosed = 30¿years old.
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2021 |
Graham SE, Clarke SL, Wu K-HH, Kanoni S, Zajac GJM, Ramdas S, et al., 'The power of genetic diversity in genome-wide association studies of lipids', NATURE, 600 675-+ (2021) [C1]
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Nova |
2021 |
Wiik MU, Evans T-J, Belhadj S, Bolton KA, Dymerska D, Jagmohan-Changur S, et al., 'A genetic variant in telomerase reverse transcriptase (TERT) modifies cancer risk in Lynch syndrome patients harbouring pathogenic MSH2 variants.', Scientific reports, 11 11401 (2021) [C1]
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2021 |
Hryhorowicz S, Kaczmarek-Rys M, Zielinska A, Scott RJ, Slomski R, Plawski A, 'Endocannabinoid System as a Promising Therapeutic Target in Inflammatory Bowel Disease - A Systematic Review', FRONTIERS IN IMMUNOLOGY, 12 (2021) [C1]
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Nova |
2021 |
Campagna MP, Xavier A, Lechner-Scott J, Maltby V, Scott RJ, Butzkueven H, et al., 'Epigenome-wide association studies: current knowledge, strategies and recommendations', CLINICAL EPIGENETICS, 13 (2021) [C1]
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2021 |
Kho PF, Wang X, Cuellar-Partida G, Dork T, Goode EL, Lambrechts D, et al., 'Multi-tissue transcriptome-wide association study identifies eight candidate genes and tissue-specific gene expression underlying endometrial cancer susceptibility', COMMUNICATIONS BIOLOGY, 4 (2021) [C1]
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2021 |
Zlowocka-Perlowska E, Debniak T, Slojewski M, van de Wetering T, Toloczko-Grabarek A, Cybulski C, et al., 'Survival of bladder or renal cancer in patients with CHEK2 mutations', PLOS ONE, 16 (2021) [C1]
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2021 |
Griffin C, Vilain R, King S, Nixon S, Gooley A, Bray S, et al., 'Mind Over Matter: Confronting Challenges in Post-Mortem Brain Biobanking for Glioblastoma Multiforme', Biomarker Insights, 16 (2021) [C1]
Over the past 10 years, there has been limited progress for the treatment of brain cancer and outcomes for patients are not much improved. For brain cancer researchers, a major ob... [more]
Over the past 10 years, there has been limited progress for the treatment of brain cancer and outcomes for patients are not much improved. For brain cancer researchers, a major obstacle to biomarker driven research is limited access to brain cancer tissue for research purposes. The Mark Hughes Foundation Brain Biobank is one of the first post-mortem adult brain banks in Australia to operate with protocols specifically developed for brain cancer. Located within the Hunter New England Local Health District and operated by Hunter Cancer Biobank, the boundaries of service provided by the Brain Bank extend well into the surrounding regional and rural areas of the Local Health District and beyond. Brain cancer biobanking is challenging. There are conflicting international guidelines for best practice and unanswered questions relating to scientific, psychosocial and operational practices. To address this challenge, a best practice model was developed, informed by a consensus of existing data but with consideration of the difficulties associated with operating in regional or resource poor settings. The regional application of this model was challenged following the presentation of a donor located in a remote area, 380km away from the biobank. This required biobank staff to overcome numerous obstacles including long distance patient transport, lack of palliative care staff, death in the home and limited rural outreach services. Through the establishment of shared goals, contingency planning and the development of an informal infrastructure, the donation was facilitated within the required timeframe. This experience demonstrates the importance of collaboration and networking to overcome resource insufficiency and geographical challenges in rural cancer research programmes.
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Nova |
2021 |
Li N, Zethoven M, McInerny S, Devereux L, Huang YK, Thio N, et al., 'Evaluation of the association of heterozygous germline variants in NTHL1 with breast cancer predisposition: an international multi-center study of 47,180 subjects', npj Breast Cancer, 7 (2021) [C1]
Bi-allelic loss-of-function (LoF) variants in the base excision repair (BER) gene NTHL1 cause a high-risk hereditary multi-tumor syndrome that includes breast cancer, but the cont... [more]
Bi-allelic loss-of-function (LoF) variants in the base excision repair (BER) gene NTHL1 cause a high-risk hereditary multi-tumor syndrome that includes breast cancer, but the contribution of heterozygous variants to hereditary breast cancer is unknown. An analysis of 4985 women with breast cancer, enriched for familial features, and 4786 cancer-free women revealed significant enrichment for NTHL1 LoF variants. Immunohistochemistry confirmed reduced NTHL1 expression in tumors from heterozygous carriers but the NTHL1 bi-allelic loss characteristic mutational signature (SBS 30) was not present. The analysis was extended to 27,421 breast cancer cases and 19,759 controls from 10 international studies revealing 138 cases and 93 controls with a heterozygous LoF variant (OR 1.06, 95% CI: 0.82¿1.39) and 316 cases and 179 controls with a missense variant (OR 1.31, 95% CI: 1.09¿1.57). Missense variants selected for deleterious features by a number of in silico bioinformatic prediction tools or located within the endonuclease III functional domain showed a stronger association with breast cancer. Somatic sequencing of breast cancers from carriers indicated that the risk associated with NTHL1 appears to operate through haploinsufficiency, consistent with other described low-penetrance breast cancer genes. Data from this very large international multicenter study suggests that heterozygous pathogenic germline coding variants in NTHL1 may be associated with low- to moderate- increased risk of breast cancer.
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2021 |
White C, Scott RJ, Paul C, Ziolkowski A, Mossman D, Ackland S, 'Ethnic Diversity of DPD Activity and the DPYD Gene: Review of the Literature', PHARMACOGENOMICS & PERSONALIZED MEDICINE, 14 1603-1617 (2021) [C1]
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2021 |
Baszuk P, Janasik B, Pietrzak S, Marciniak W, Reszka E, Bialkowska K, et al., 'Lung Cancer Occurrence Correlation with Serum Chromium Levels and Genotypes', Biological Trace Element Research, 199 1228-1236 (2021) [C1]
Lung cancer is the leading cause of cancer-related death worldwide. Exposure to environmental and occupational carcinogens is an important cause of lung cancer. One of these subst... [more]
Lung cancer is the leading cause of cancer-related death worldwide. Exposure to environmental and occupational carcinogens is an important cause of lung cancer. One of these substances is chromium, which is found ubiquitously across the planet. The International Agency for Research on Cancer has classified chromium(VI) as a human carcinogen. The aim of this study was to assess whether serum chromium levels, as well as DNA variants in selected genes involved in carcinogenesis, xenobiotic-metabolism, and oxidative stress could be helpful in the detection of lung cancer. We conducted a study using 218 lung cancer patients and 218 matched healthy controls. We measured serum chromium levels and genotyped ten genetic variants in ERCC2, XRCC1, MT1B, GSTP1, ABCB1, NQ01, CRTC3, GPX1, SOD2 and CAT. The odds ratios of being diagnosed with lung cancer were calculated using conditional logistic regression with respect to serum chromium level and genotypes. The odds ratio for the occurrence of lung cancer increased with increasing serum chromium levels. The difference between the quartiles with the lowest vs. highest chromium level was more than fourfold in the entire group (OR 4.52, CI 2.17¿9.42, p < 0.01). This correlation was significantly increased by more than twice when specific genotypes were taken into consideration (ERCC¿rs12181 TT, OR 12.34, CI 1.17¿130.01, p = 0.04; CRTC3¿rs12915189 non GG, OR 9.73, CI 1.58¿60.10, p = 0.01; GSTP1¿rs1695 non AA, OR 9.47, CI 2.06¿43.49, p = < 0.01; CAT¿rs1001179 non CC, OR 9.18, CI 1.64¿51.24, p = 0.01). Total serum chromium levels > 0.1¿µg/L were correlated with 73% (52/71) of lung cancers diagnosed with stage I disease. Our findings support the role of chromium and the influence of key proteins on lung cancer burden in the general population.
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2021 |
Pariyar M, Johns A, Thorne RF, Scott RJ, Avery-Kiejda KA, 'Copy number variation in triple negative breast cancer samples associated with lymph node metastasis', Neoplasia (United States), 23 743-753 (2021) [C1]
Triple negative breast cancer (TNBC) is a highly metastatic and aggressive subtype of breast cancer and cases presenting with lymph node involvement have worse outcomes. This stud... [more]
Triple negative breast cancer (TNBC) is a highly metastatic and aggressive subtype of breast cancer and cases presenting with lymph node involvement have worse outcomes. This study aimed to determine the regions of copy number variation (CNV) associated with lymph node metastasis in TNBC patients. CNV analyses were performed in a study cohort of 23 invasive ductal carcinomas (IDCs), 12 lymph node metastases (LNmets), and 7 normal adjacent tissues (NATs); as well as in an independent cohort containing 70 TNBC IDCs and the same 7 NATs. CNV-associated genes were analyzed using GO-enrichment and Pathway analysis. The prognostic role for genes showing CNV-based changes in messenger RNA expression was determined using the Kaplan-Meier plotter database. For the IDCs, there were a number of variations that were common in both the study and independent cohorts in the amplified regions of 1q, 8q, 19 (p and q), 2p, 5p and the deleted regions in 8p followed by 5q, and 19p. The most frequently amplified regions in the LNmets of the study cohort were 4q28.3, 2p, 3q24, 1q21.2, 10p, 12p11.1, 8q, 20p11.22-20p11.21, 21q22.13, 6p22.1 and the most frequently deleted regions were in 1p36.23, 4q21.1 and 5q. A total of 686 (441 amplified and 245 deleted) genes were associated with LNmets. The LNmet-associated genes were highly enriched for ¿regulation of complement activation,¿ ¿regulation of protein activation cascade,¿ ¿regulation of humoral immune response,¿ ¿oxytocin signalling pathway,¿ and ¿TRAIL binding¿ pathways. Moreover, 6/686 LNmet-associated genes showed CNV-based changes in their mRNA expression of which, high expression of ASPM and KIF14 was significantly associated with worse relapse-free survival. This study has identified several CNV regions in TNBC that could play a major role in metastasis to the lymph node.
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2021 |
Kho PF, Mortlock S, Rogers PAW, Nyholt DR, Montgomery GW, Spurdle AB, et al., 'Genetic analyses of gynecological disease identify genetic relationships between uterine fibroids and endometrial cancer, and a novel endometrial cancer genetic risk region at the
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2021 |
Reay WR, El Shair S, Geaghan MP, Riveros C, Holliday EG, McEvoy MA, et al., 'Genetic association and causal inference converge on hyperglycaemia as a modifiable factor to improve lung function', ELIFE, 10 (2021) [C1]
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Nova |
2021 |
Lubinski J, Jaworowska E, Derkacz R, Marciniak W, Bialkowska K, Baszuk P, et al., 'Survival of laryngeal cancer patients depending on zinc serum level and oxidative stress genotypes', Biomolecules, 11 (2021) [C1]
Stress contributes to various aspects of malignancy and could influence survival in laryngeal cancer patients. Among antioxidant mechanisms, zinc and the antioxidant enzymes super... [more]
Stress contributes to various aspects of malignancy and could influence survival in laryngeal cancer patients. Among antioxidant mechanisms, zinc and the antioxidant enzymes superoxide dismutase 2, catalase and glutathione peroxidase 1 play a major role. The aim of this study was a prospective evaluation of the survival of patients with laryngeal cancer in relation to serum levels of zinc in combination with functional genotype differences of three key antioxidant enzymes. The study group consisted of 300 patients treated surgically for laryngeal cancer. Serum zinc levels and common polymorphisms in SOD2, CAT and GPX1 were analyzed. The risk of death in patients with the lowest zinc levels was increased in comparison with patients with the highest levels. Polymorphisms of antioxidant genes by themselves were not correlated with survival, however, serum zinc level impact on survival was stronger for SOD2 TC/TT and CAT CC variants. GPX1 polymorphisms did not correlate with zinc levels regarding survival. In conclusion, serum zinc concentration appears to be an important prognostic factor for survival of patients diagnosed with laryngeal cancer. When higher zinc levels were correlated with polymorphisms in SOD2 and CAT a further increase in survival was observed.
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2021 |
Butler T, Schofield PW, Knight L, Ton B, Greenberg D, Scott RJ, et al., 'Sertraline hydrochloride for reducing impulsive behaviour in male, repeat-violent offenders (ReINVEST): protocol for a phase IV, double-blind, placebo-controlled, randomised clinical trial', BMJ OPEN, 11 (2021)
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2021 |
Morra A, Escala-Garcia M, Beesley J, Keeman R, Canisius S, Ahearn TU, et al., 'Association of germline genetic variants with breast cancer-specific survival in patient subgroups defined by clinic-pathological variables related to tumor biology and type of systemic treatment.', Breast cancer research : BCR, 23 86 (2021) [C1]
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2021 |
Baszuk P, Stadnik P, Marciniak W, Derkacz R, Jakubowska A, Cybulski C, et al., 'Low blood-as levels and selected genotypes appears to be promising biomarkers for occurrence of colorectal cancer in women', Biomedicines, 9 (2021) [C1]
In following study we examined whether blood arsenic (As) levels combined with specific polymorphisms in MT1B, GSTP1, ABCB1, NQO1, CRTC3, GPX1, SOD2, CAT, XRCC1, ERCC2 can be used... [more]
In following study we examined whether blood arsenic (As) levels combined with specific polymorphisms in MT1B, GSTP1, ABCB1, NQO1, CRTC3, GPX1, SOD2, CAT, XRCC1, ERCC2 can be used as a marker for the detection of colorectal cancer (CRC) among Polish women. A retrospective case-control study of CRC included 83 CRC cases and 78 healthy controls. From each study participant pre-treatment peripheral blood was collected for As level measurement by inductively coupled¿ plasma mass spectrometry (ICP-MS). We estimated the odds ratio (OR) of the association between blood-As levels and CRC using multivariable unconditional logistic regression models. A low blood-As level (0.27¿0.67 µg/L) was associated with an increased frequency of CRC (OR: 3.69; p = 0.005). This correlation was significantly greater when participants carried particular gene variants: CAT, rs1001179-nonCC (OR: 19.4; p = 0.001); ABCB1 rs2032582¿CC (OR: 14.8; p = 0.024); GPX1 rs1050450-CC (OR: 11.6; p = 0.002) and CRTC3 rs12915189-nonGG (OR: 10.3; p = 0.003). Our study provides strong evidence that low blood-As levels are significantly associated with increased CRC occurrence and that particular gene variants significantly enhanced this correlation however, due to the novelty of these findings, we suggest further validation before a definitive statement that the combined effect of low blood-As levels with specific gene polymorphisms is a suitable CRC biomarker.
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Nova |
2021 |
Xavier A, Scott RJ, Talseth-Palmer B, 'Exome sequencing of familial adenomatous polyposis-like individuals identifies both known and novel causative genes', CLINICAL GENETICS, 100 478-483 (2021) [C1]
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Nova |
2021 |
Mullins N, Forstner AJ, O'Connell KS, Coombes B, Coleman JR, Qiao Z, et al., 'Genome-wide association study of more than 40,000 bipolar disorder cases provides new insights into the underlying biology', NATURE GENETICS, 53 817-+ (2021) [C1]
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Nova |
2021 |
Jenkins MA, 'Variation in the risk of colorectal cancer in families with Lynch syndrome: a retrospective cohort study', LANCET ONCOLOGY, 22 1014-1022 (2021) [C1]
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2021 |
Connor T, McPhillips M, Hipwell M, Ziolkowski A, Oldmeadow C, Clapham M, et al., 'CD36 polymorphisms and the age of disease onset in patients with pathogenic variants within the mutation cluster region of APC', HEREDITARY CANCER IN CLINICAL PRACTICE, 19 (2021) [C1]
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Nova |
2021 |
Li N, Lim BWX, Thompson ER, McInerny S, Zethoven M, Cheasley D, et al., 'Investigation of monogenic causes of familial breast cancer: data from the BEACCON case-control study', NPJ BREAST CANCER, 7 (2021) [C1]
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2020 |
Hess JL, Tylee DS, Barve R, de Jong S, Ophoff RA, Kumarasinghe N, et al., 'Transcriptomic abnormalities in peripheral blood in bipolar disorder, and discrimination of the major psychoses', Schizophrenia Research, 217 124-135 (2020) [C1]
We performed a transcriptome-wide meta-analysis and gene co-expression network analysis to identify genes and gene networks dysregulated in the peripheral blood of bipolar disorde... [more]
We performed a transcriptome-wide meta-analysis and gene co-expression network analysis to identify genes and gene networks dysregulated in the peripheral blood of bipolar disorder (BD) cases relative to unaffected comparison subjects, and determined the specificity of the transcriptomic signatures of BD and schizophrenia (SZ). Nineteen genes and 4 gene modules were significantly differentially expressed in BD cases. Thirteen gene modules were shown to be differentially expressed in a combined case-group of BD and SZ subjects called ¿major psychosis¿, including genes biologically linked to apoptosis, reactive oxygen, chromatin remodeling, and immune signaling. No modules were differentially expressed between BD and SZ cases. Machine-learning classifiers trained to separate diagnostic classes based solely on gene expression profiles could distinguish BD cases from unaffected comparison subjects with an area under the curve (AUC) of 0.724, as well as BD cases from SZ cases with AUC = 0.677 in withheld test samples. We introduced a novel and straightforward method called ¿polytranscript risk scoring¿ that could distinguish BD cases from unaffected subjects (AUC = 0.672) and SZ cases (AUC = 0.607) significantly better than expected by chance. Taken together, our results highlighted gene expression alterations common to BD and SZ that involve biological processes of inflammation, oxidative stress, apoptosis, and chromatin regulation, and highlight disorder-specific changes in gene expression that discriminate the major psychoses.
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2020 |
Berry NK, Scott RJ, Sutton R, Law T, Trahair TN, Dalla-Pozza L, et al., 'Enrichment of atypical hyperdiploidy and IKZF1 deletions detected by SNP-microarray in high-risk Australian AIEOP-BFM B-cell acute lymphoblastic leukaemia cohort', Cancer Genetics, 242 8-14 (2020) [C1]
Acute lymphoblastic leukaemia (ALL) is the most common childhood malignancy with the majority of patients being classified as B-cell lineage (B-ALL). The sub-classification of B-A... [more]
Acute lymphoblastic leukaemia (ALL) is the most common childhood malignancy with the majority of patients being classified as B-cell lineage (B-ALL). The sub-classification of B-ALL is based on genomic architecture. Recent studies have demonstrated the capability of SNP-microarrays to detect genomic changes in B-ALL which cannot be observed by conventional cytogenetic methods. In current clinical trials, B-ALL patients at high risk of relapse are mainly identified by adverse cancer genomics and/or poor response to early therapy. To test the hypothesis that inclusion of SNP-microarrays in frontline diagnostics could more efficiently and accurately identify adverse genomic factors than conventional techniques, we evaluated the Australian high-risk B-ALL cohort enrolled on AIEOP-BFM ALL 2009 study (n = 33). SNP-microarray analysis identified additional aberrations in 97% of patients (32/33) compared to conventional techniques. This changed the genomic risk category of 24% (8/33) of patients. Additionally, 27% (9/33) of patients exhibited a ¿hyperdiploid¿ genome, which is generally associated with a good genomic risk and favourable outcomes. An enrichment of IKZF1 deletions was observed with one third of the cohort affected. Our findings suggest the current classification system could be improved and highlights the need to use more sensitive techniques such as SNP-microarray for cytogenomic risk stratification in B-ALL.
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2020 |
Grasby KL, Jahanshad N, Painter JN, Colodro-Conde L, Bralten J, Hibar DP, et al., 'The genetic architecture of the human cerebral cortex', SCIENCE, 367 1340-+ (2020) [C1]
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Nova |
2020 |
Feng H, Gusev A, Pasaniuc B, Wu L, Long J, Abu-full Z, et al., 'Transcriptome-wide association study of breast cancer risk by estrogen-receptor status', Genetic Epidemiology, 44 442-468 (2020) [C1]
Previous transcriptome-wide association studies (TWAS) have identified breast cancer risk genes by integrating data from expression quantitative loci and genome-wide association s... [more]
Previous transcriptome-wide association studies (TWAS) have identified breast cancer risk genes by integrating data from expression quantitative loci and genome-wide association studies (GWAS), but analyses of breast cancer subtype-specific associations have been limited. In this study, we conducted a TWAS using gene expression data from GTEx and summary statistics from the hitherto largest GWAS meta-analysis conducted for breast cancer overall, and by estrogen receptor subtypes (ER+ and ER-). We further compared associations with ER+ and ER- subtypes, using a case-only TWAS approach. We also conducted multigene conditional analyses in regions with multiple TWAS associations. Two genes, STXBP4 and HIST2H2BA, were specifically associated with ER+ but not with ER¿ breast cancer. We further identified 30 TWAS-significant genes associated with overall breast cancer risk, including four that were not identified in previous studies. Conditional analyses identified single independent breast-cancer gene in three of six regions harboring multiple TWAS-significant genes. Our study provides new information on breast cancer genetics and biology, particularly about genomic differences between ER+ and ER- breast cancer.
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2020 |
Malinska K, Deptula J, Rogozoza-Janiszewska E, Gorski B, Scott R, Rudnicka H, et al., 'Constitutional variants inPOT1,TERF2IP, andACDgenes in patients with melanoma in the Polish population', EUROPEAN JOURNAL OF CANCER PREVENTION, 29 511-519 (2020) [C1]
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Nova |
2020 |
Feng YC, Liu XY, Teng L, Ji Q, Wu Y, Li JM, et al., 'c-Myc inactivation of p53 through the pan-cancer lncRNA MILIP drives cancer pathogenesis', Nature Communications, 11 (2020) [C1]
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2020 |
Kramer I, Hooning MJ, Mavaddat N, Hauptmann M, Keeman R, Steyerberg EW, et al., 'Breast Cancer Polygenic Risk Score and Contralateral Breast Cancer Risk', American Journal of Human Genetics, 107 837-848 (2020) [C1]
Previous research has shown that polygenic risk scores (PRSs) can be used to stratify women according to their risk of developing primary invasive breast cancer. This study aimed ... [more]
Previous research has shown that polygenic risk scores (PRSs) can be used to stratify women according to their risk of developing primary invasive breast cancer. This study aimed to evaluate the association between a recently validated PRS of 313 germline variants (PRS313) and contralateral breast cancer (CBC) risk. We included 56,068 women of European ancestry diagnosed with first invasive breast cancer from 1990 onward with follow-up from the Breast Cancer Association Consortium. Metachronous CBC risk (N = 1,027) according to the distribution of PRS313 was quantified using Cox regression analyses. We assessed PRS313 interaction with age at first diagnosis, family history, morphology, ER status, PR status, and HER2 status, and (neo)adjuvant therapy. In studies of Asian women, with limited follow-up, CBC risk associated with PRS313 was assessed using logistic regression for 340 women with CBC compared with 12,133 women with unilateral breast cancer. Higher PRS313 was associated with increased CBC risk: hazard ratio per standard deviation (SD) = 1.25 (95%CI = 1.18¿1.33) for Europeans, and an OR per SD = 1.15 (95%CI = 1.02¿1.29) for Asians. The absolute lifetime risks of CBC, accounting for death as competing risk, were 12.4% for European women at the 10th percentile and 20.5% at the 90th percentile of PRS313. We found no evidence of confounding by or interaction with individual characteristics, characteristics of the primary tumor, or treatment. The C-index for the PRS313 alone was 0.563 (95%CI = 0.547¿0.586). In conclusion, PRS313 is an independent factor associated with CBC risk and can be incorporated into CBC risk prediction models to help improve stratification and optimize surveillance and treatment strategies.
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2020 |
Burn J, Sheth H, Elliott F, Reed L, Macrae F, Mecklin JP, et al., 'Cancer prevention with aspirin in hereditary colorectal cancer (Lynch syndrome), 10-year follow-up and registry-based 20-year data in the CAPP2 study: a double-blind, randomised, placebo-controlled trial', The Lancet, 395 1855-1863 (2020) [C1]
Background: Lynch syndrome is associated with an increased risk of colorectal cancer and with a broader spectrum of cancers, especially endometrial cancer. In 2011, our group repo... [more]
Background: Lynch syndrome is associated with an increased risk of colorectal cancer and with a broader spectrum of cancers, especially endometrial cancer. In 2011, our group reported long-term cancer outcomes (mean follow-up 55·7 months [SD 31·4]) for participants with Lynch syndrome enrolled into a randomised trial of daily aspirin versus placebo. This report completes the planned 10-year follow-up to allow a longer-term assessment of the effect of taking regular aspirin in this high-risk population. Methods: In the double-blind, randomised CAPP2 trial, 861 patients from 43 international centres worldwide (707 [82%] from Europe, 112 [13%] from Australasia, 38 [4%] from Africa, and four [<1%] from The Americas) with Lynch syndrome were randomly assigned to receive 600 mg aspirin daily or placebo. Cancer outcomes were monitored for at least 10 years from recruitment with English, Finnish, and Welsh participants being monitored for up to 20 years. The primary endpoint was development of colorectal cancer. Analysis was by intention to treat and per protocol. The trial is registered with the ISRCTN registry, number ISRCTN59521990. Findings: Between January, 1999, and March, 2005, 937 eligible patients with Lynch syndrome, mean age 45 years, commenced treatment, of whom 861 agreed to be randomly assigned to the aspirin group or placebo; 427 (50%) participants received aspirin and 434 (50%) placebo. Participants were followed for a mean of 10 years approximating 8500 person-years. 40 (9%) of 427 participants who received aspirin developed colorectal cancer compared with 58 (13%) of 434 who received placebo. Intention-to-treat Cox proportional hazards analysis revealed a significantly reduced hazard ratio (HR) of 0·65 (95% CI 0·43¿0·97; p=0·035) for aspirin versus placebo. Negative binomial regression to account for multiple primary events gave an incidence rate ratio of 0·58 (0·39¿0·87; p=0·0085). Per-protocol analyses restricted to 509 who achieved 2 years' intervention gave an HR of 0·56 (0·34¿0·91; p=0·019) and an incidence rate ratio of 0·50 (0·31¿0·82; p=0·0057). Non-colorectal Lynch syndrome cancers were reported in 36 participants who received aspirin and 36 participants who received placebo. Intention-to-treat and per-protocol analyses showed no effect. For all Lynch syndrome cancers combined, the intention-to-treat analysis did not reach significance but per-protocol analysis showed significantly reduced overall risk for the aspirin group (HR=0·63, 0·43¿0·92; p=0·018). Adverse events during the intervention phase between aspirin and placebo groups were similar, and no significant difference in compliance between intervention groups was observed for participants with complete intervention phase data; details reported previously. Interpretation: The case for prevention of colorectal cancer with aspirin in Lynch syndrome is supported by our results. Funding: Cancer Research UK, European Union, MRC, NIHR, Bayer Pharma AG, Barbour Foundation.
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Nova |
2020 |
Shu X, Bao J, Wu L, Long J, Shu XO, Guo X, et al., 'Evaluation of associations between genetically predicted circulating protein biomarkers and breast cancer risk', International Journal of Cancer, 146 2130-2138 (2020) [C1]
A small number of circulating proteins have been reported to be associated with breast cancer risk, with inconsistent results. Herein, we attempted to identify novel protein bioma... [more]
A small number of circulating proteins have been reported to be associated with breast cancer risk, with inconsistent results. Herein, we attempted to identify novel protein biomarkers for breast cancer via the integration of genomics and proteomics data. In the Breast Cancer Association Consortium (BCAC), with 122,977 cases and 105,974 controls of European descendants, we evaluated the associations of the genetically predicted concentrations of >1,400 circulating proteins with breast cancer risk. We used data from a large-scale protein quantitative trait loci (pQTL) analysis as our study instrument. Summary statistics for these pQTL variants related to breast cancer risk were obtained from the BCAC and used to estimate odds ratios (OR) for each protein using the inverse-variance weighted method. We identified 56 proteins significantly associated with breast cancer risk by instrumental analysis (false discovery rate <0.05). Of these, the concentrations of 32 were influenced by variants close to a breast cancer susceptibility locus (ABO, 9q34.2). Many of these proteins, such as insulin receptor, insulin-like growth factor receptor 1 and other membrane receptors (OR: 0.82¿1.18, p values: 6.96 × 10-4¿3.28 × 10-8), are linked to insulin resistance and estrogen receptor signaling pathways. Proteins identified at other loci include those involved in biological processes such as alcohol and lipid metabolism, proteolysis, apoptosis, immune regulation and cell motility and proliferation. Consistent associations were observed for 22 proteins in the UK Biobank data (p < 0.05). The study identifies potential novel biomarkers for breast cancer, but further investigation is needed to replicate our findings.
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Nova |
2020 |
Groen K, Maltby VE, Scott RJ, Tajouri L, Lechner-Scott J, 'Erythrocyte microRNAs show biomarker potential and implicate multiple sclerosis susceptibility genes.', Clinical and translational medicine, 10 74-90 (2020) [C1]
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Nova |
2020 |
Reay W, Shair SE, Geaghan M, Riveros C, Holliday E, McEvoy M, et al., 'Genetically informed precision drug repurposing for lung function and implications for respiratory infection (2020)
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2020 |
Kamitaki N, Sekar A, Handsaker RE, de Rivera H, Tooley K, Morris DL, et al., 'Complement genes contribute sex-biased vulnerability in diverse disorders', Nature, 582 577-581 (2020) [C1]
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Nova |
2020 |
Radua J, Vieta E, Shinohara R, Kochunov P, Quidé Y, Green MJ, et al., 'Increased power by harmonizing structural MRI site differences with the ComBat batch adjustment method in ENIGMA', NeuroImage, 218 (2020) [C1]
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Nova |
2020 |
Maltby VE, Lea RA, Burnard S, Xavier A, Van Cao T, White N, et al., 'Epigenetic differences at the
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Nova |
2020 |
Fachal L, Aschard H, Beesley J, Barnes DR, Allen J, Kar S, et al., 'Fine-mapping of 150 breast cancer risk regions identifies 191 likely target genes', Nature Genetics, 52 56-73 (2020) [C1]
Genome-wide association studies have identified breast cancer risk variants in over 150 genomic regions, but the mechanisms underlying risk remain largely unknown. These regions w... [more]
Genome-wide association studies have identified breast cancer risk variants in over 150 genomic regions, but the mechanisms underlying risk remain largely unknown. These regions were explored by combining association analysis with in silico genomic feature annotations. We defined 205 independent risk-associated signals with the set of credible causal variants in each one. In parallel, we used a Bayesian approach (PAINTOR) that combines genetic association, linkage disequilibrium and enriched genomic features to determine variants with high posterior probabilities of being causal. Potentially causal variants were significantly over-represented in active gene regulatory regions and transcription factor binding sites. We applied our INQUSIT pipeline for prioritizing genes as targets of those potentially causal variants, using gene expression (expression quantitative trait loci), chromatin interaction and functional annotations. Known cancer drivers, transcription factors and genes in the developmental, apoptosis, immune system and DNA integrity checkpoint gene ontology pathways were over-represented among the highest-confidence target genes.
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Nova |
2020 |
Liu X, Low SK, Atkins JR, Wu JQ, Reay WR, Cairns HM, et al., 'Wnt receptor gene FZD1 was associated with schizophrenia in genome-wide SNP analysis of the Australian Schizophrenia Research Bank cohort', Australian and New Zealand Journal of Psychiatry, 54 902-908 (2020) [C1]
Objectives: Large-scale genetic analysis of common variation in schizophrenia has been a powerful approach to understanding this complex but highly heritable psychotic disorder. T... [more]
Objectives: Large-scale genetic analysis of common variation in schizophrenia has been a powerful approach to understanding this complex but highly heritable psychotic disorder. To further investigate loci, genes and pathways associated more specifically in the well-characterized Australian Schizophrenia Research Bank cohort, we applied genome-wide single-nucleotide polymorphism analysis in these three annotation categories. Methods: We performed a case¿control genome-wide association study in 429 schizophrenia samples and 255 controls. Post-genome-wide association study analyses were then integrated with genomic annotations to explore the enrichment of variation at the gene and pathway level. We also examine candidate single-nucleotide polymorphisms with potential function within expression quantitative trait loci and investigate overall enrichment of variation within tissue-specific functional regulatory domains of the genome. Results: The strongest finding (p = 2.01 × 10-6, odds ratio = 1.82, 95% confidence interval = [1.42, 2.33]) in genome-wide association study was with rs10252923 at 7q21.13, downstream of FZD1 (frizzled class receptor 1). While this did not stand alone after correction, the involvement of FZD1 was supported by gene-based analysis, which exceeded the threshold for genome-wide significance (p = 2.78 × 10-6). Conclusion: The identification of FZD1, as an independent association signal at the gene level, supports the hypothesis that the Wnt signalling pathway is altered in the pathogenesis of schizophrenia and may be an important target for therapeutic development.
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Nova |
2020 |
Groen K, Maltby VE, Scott RJ, Tajouri L, Lechner-Scott J, 'Concentrations of plasma-borne extracellular particles differ between multiple sclerosis disease courses and compared to healthy controls', Multiple Sclerosis and Related Disorders, 45 (2020) [C1]
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Nova |
2019 |
Geaghan MP, Atkins JR, Brichta AM, Tooney PA, Scott RJ, Carr VJ, Cairns MJ, 'Alteration of miRNA-mRNA interactions in lymphocytes of individuals with schizophrenia', Journal of Psychiatric Research, 112 89-98 (2019) [C1]
The aetiology of schizophrenia is complex, heterogeneous, and involves interplay of many genetic and environmental influences. While significant progress has been made in the unde... [more]
The aetiology of schizophrenia is complex, heterogeneous, and involves interplay of many genetic and environmental influences. While significant progress has been made in the understanding the common heritable component, we are still grappling with the genomic encoding of environmental risk. One class of molecule that has tremendous potential is miRNA. These molecules are regulated by genetic and environmental factors associated with schizophrenia and have a very significant impact on temporospatial patterns of gene expression. To better understand the relationship between miRNA and gene expression in the disorder we analysed these molecules in RNA isolated from peripheral blood mononuclear cells (PBMCs) obtained from an Australian cohort of 36 individuals with schizophrenia and 15 healthy controls using next-generation RNA sequencing. Significant changes in both mRNA and miRNA expression profiles were observed implicating important interaction networks involved in immune activity and development. We also observed sexual dimorphism, particularly in relation to variation in mRNA, with males showing significantly more differentially expressed genes. Interestingly, while we explored expression in lymphocytes, the systems biology of miRNA-mRNA interactions was suggestive of significant pleiotropy with enrichment of networks related to neuronal activity.
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Nova |
2019 |
Morten BC, Chiu S, Oldmeadow C, Lubinski J, Scott RJ, Avery-Kiejda KA, 'The intron 3 16 bp duplication polymorphism of p53 (rs17878362) is not associated with increased risk of developing triple-negative breast cancer', Breast Cancer Research and Treatment, 173 727-733 (2019) [C1]
Purpose: Very little is known about the genetic risk factors associated with triple-negative breast cancer (TNBC), an aggressive clinical subtype characterised by the absence of E... [more]
Purpose: Very little is known about the genetic risk factors associated with triple-negative breast cancer (TNBC), an aggressive clinical subtype characterised by the absence of ER, PR and HER2. p53, the tumour suppressor gene, is essential for maintaining genomic stability in response to cellular stress. In breast cancer, the mutation rates of TP53 vary depending on the subtype, such that ER-negative tumours have a high rate, and in ER-positive tumours they are less common. Previous studies have implicated the intronic polymorphism in TP53 (rs17878362; or PIN3) with an increased risk of developing breast cancer, although little has been discerned on its prevalence in different subtypes. In this study, we investigated the prevalence of the PIN3 genotype in the blood of cohorts with ER-positive and the ER-negative subtype TNBC, and assessed its association with outcome. Methods: We genotyped 656 TNBC and 648 ER-positive breast cancer patients, along with 436 controls, and compared the prevalence of polymorphism rs17878362 in these cohorts. Results: We found there to be no differences in the prevalence of the PIN3 genotype between the ER-positive and TNBC cohorts. Furthermore, no statistically significant difference was observed in the outcome of patients in either cohort with respect to their PIN3 genotype. Conclusions: Taken together, our results do not support an association of the PIN3 genotype with increased breast cancer risk, either in ER-positive or ER-negative patients.
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Nova |
2019 |
Davies G, Lam M, Harris SE, Trampush JW, Luciano M, Hill WD, et al., 'Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function (vol 9, 2098, 2018)', NATURE COMMUNICATIONS, 10 (2019)
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2019 |
Lee PH, Anttila V, Won H, Feng YCA, Rosenthal J, Zhu Z, et al., 'Genomic Relationships, Novel Loci, and Pleiotropic Mechanisms across Eight Psychiatric Disorders', Cell, 179 1469-1482.e11 (2019) [C1]
Genetic influences on psychiatric disorders transcend diagnostic boundaries, suggesting substantial pleiotropy of contributing loci. However, the nature and mechanisms of these pl... [more]
Genetic influences on psychiatric disorders transcend diagnostic boundaries, suggesting substantial pleiotropy of contributing loci. However, the nature and mechanisms of these pleiotropic effects remain unclear. We performed analyses of 232,964 cases and 494,162 controls from genome-wide studies of anorexia nervosa, attention-deficit/hyperactivity disorder, autism spectrum disorder, bipolar disorder, major depression, obsessive-compulsive disorder, schizophrenia, and Tourette syndrome. Genetic correlation analyses revealed a meaningful structure within the eight disorders, identifying three groups of inter-related disorders. Meta-analysis across these eight disorders detected 109 loci associated with at least two psychiatric disorders, including 23 loci with pleiotropic effects on four or more disorders and 11 loci with antagonistic effects on multiple disorders. The pleiotropic loci are located within genes that show heightened expression in the brain throughout the lifespan, beginning prenatally in the second trimester, and play prominent roles in neurodevelopmental processes. These findings have important implications for psychiatric nosology, drug development, and risk prediction.
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Nova |
2019 |
Escala-Garcia M, Guo Q, Dörk T, Canisius S, Keeman R, Dennis J, et al., 'Genome-wide association study of germline variants and breast cancer-specific mortality', British Journal of Cancer, 120 647-657 (2019) [C1]
Background: We examined the associations between germline variants and breast cancer mortality using a large meta-analysis of women of European ancestry. Methods: Meta-analyses in... [more]
Background: We examined the associations between germline variants and breast cancer mortality using a large meta-analysis of women of European ancestry. Methods: Meta-analyses included summary estimates based on Cox models of twelve datasets using ~10.4 million variants for 96,661 women with breast cancer and 7697 events (breast cancer-specific deaths). Oestrogen receptor (ER)-specific analyses were based on 64,171 ER-positive (4116) and 16,172 ER-negative (2125) patients. We evaluated the probability of a signal to be a true positive using the Bayesian false discovery probability (BFDP). Results: We did not find any variant associated with breast cancer-specific mortality at P < 5 × 10 -8 . For ER-positive disease, the most significantly associated variant was chr7:rs4717568 (BFDP = 7%, P = 1.28 × 10 -7 , hazard ratio [HR] = 0.88, 95% confidence interval [CI] = 0.84¿0.92); the closest gene is AUTS2. For ER-negative disease, the most significant variant was chr7:rs67918676 (BFDP = 11%, P = 1.38 × 10 -7 , HR = 1.27, 95% CI = 1.16¿1.39); located within a long intergenic non-coding RNA gene (AC004009.3), close to the HOXA gene cluster. Conclusions: We uncovered germline variants on chromosome 7 at BFDP < 15% close to genes for which there is biological evidence related to breast cancer outcome. However, the paucity of variants associated with mortality at genome-wide significance underpins the challenge in providing genetic-based individualised prognostic information for breast cancer patients.
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Nova |
2019 |
Iglesias AI, Mishra A, Vitart V, Bykhovskaya Y, Hoehn R, Springelkamp H, et al., 'Cross-ancestry genome-wide association analysis of corneal thickness strengthens link between complex and Mendelian eye diseases (vol 9, 1864, 2018)', NATURE COMMUNICATIONS, 10 (2019)
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2019 |
Rammos A, Gonzalez LAN, Weinberger DR, Mitchell KJ, Nicodemus KK, 'The role of polygenic risk score gene-set analysis in the context of the omnigenic model of schizophrenia', NEUROPSYCHOPHARMACOLOGY, 44 1562-1569 (2019) [C1]
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Nova |
2019 |
Xavier A, Olsen MF, Lavik LA, Johansen J, Singh AK, Sjursen W, et al., 'Comprehensive mismatch repair gene panel identifies variants in patients with Lynch-like syndrome', MOLECULAR GENETICS & GENOMIC MEDICINE, 7 (2019) [C1]
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Nova |
2019 |
Hnatyszyn A, Hryhorowicz S, Kaczmarek-Rys M, Lis E, Slomski R, Scott RJ, Plawski A, 'Colorectal carcinoma in the course of inflammatory bowel diseases.', Hered Cancer Clin Pract, 17 18 (2019) [C1]
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Nova |
2019 |
Huckins LM, Dobbyn A, Ruderfer DM, Hoffman G, Wang W, Pardiñas AF, et al., 'Gene expression imputation across multiple brain regions provides insights into schizophrenia risk', Nature Genetics, 51 659-674 (2019) [C1]
Transcriptomic imputation approaches combine eQTL reference panels with large-scale genotype data in order to test associations between disease and gene expression. These genic as... [more]
Transcriptomic imputation approaches combine eQTL reference panels with large-scale genotype data in order to test associations between disease and gene expression. These genic associations could elucidate signals in complex genome-wide association study (GWAS) loci and may disentangle the role of different tissues in disease development. We used the largest eQTL reference panel for the dorso-lateral prefrontal cortex (DLPFC) to create a set of gene expression predictors and demonstrate their utility. We applied DLPFC and 12 GTEx-brain predictors to 40,299 schizophrenia cases and 65,264 matched controls for a large transcriptomic imputation study of schizophrenia. We identified 413 genic associations across 13 brain regions. Stepwise conditioning identified 67 non-MHC genes, of which 14 did not fall within previous GWAS loci. We identified 36 significantly enriched pathways, including hexosaminidase-A deficiency, and multiple porphyric disorder pathways. We investigated developmental expression patterns among the 67 non-MHC genes and identified specific groups of pre- and postnatal expression.
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Nova |
2019 |
Shu X, Wu L, Khankari NK, Shu X-O, Wang TJ, Michailidou K, et al., 'Associations of obesity and circulating insulin and glucose with breast cancer risk: a Mendelian randomization analysis', INTERNATIONAL JOURNAL OF EPIDEMIOLOGY, 48 795-806 (2019) [C1]
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Nova |
2019 |
Patsopoulos NA, Baranzini SE, Santaniello A, Shoostari P, Cotsapas C, Wong G, et al., 'Multiple sclerosis genomic map implicates peripheral immune cells and microglia in susceptibility', SCIENCE, 365 1417-+ (2019) [C1]
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Nova |
2019 |
Revelas M, Thalamuthu A, Oldmeadow C, Evans T-J, Armstrong NJ, Riveros C, et al., 'Exceptional Longevity and Polygenic Risk for Cardiovascular Health', GENES, 10 (2019) [C1]
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Nova |
2019 |
McCabe MJ, Gauthier MEA, Chan CL, Thompson TJ, De Sousa SMC, Puttick C, et al., 'Development and validation of a targeted gene sequencing panel for application to disparate cancers', Scientific Reports, 9 (2019) [C1]
Next generation sequencing has revolutionised genomic studies of cancer, having facilitated the development of precision oncology treatments based on a tumour¿s molecular profile.... [more]
Next generation sequencing has revolutionised genomic studies of cancer, having facilitated the development of precision oncology treatments based on a tumour¿s molecular profile. We aimed to develop a targeted gene sequencing panel for application to disparate cancer types with particular focus on tumours of the head and neck, plus test for utility in liquid biopsy. The final panel designed through Roche/Nimblegen combined 451 cancer-associated genes (2.01 Mb target region). 136 patient DNA samples were collected for performance and application testing. Panel sensitivity and precision were measured using well-characterised DNA controls (n = 47), and specificity by Sanger sequencing of the Aryl Hydrocarbon Receptor Interacting Protein (AIP) gene in 89 patients. Assessment of liquid biopsy application employed a pool of synthetic circulating tumour DNA (ctDNA). Library preparation and sequencing were conducted on Illumina-based platforms prior to analysis with our accredited (ISO15189) bioinformatics pipeline. We achieved a mean coverage of 395x, with sensitivity and specificity of >99% and precision of >97%. Liquid biopsy revealed detection to 1.25% variant allele frequency. Application to head and neck tumours/cancers resulted in detection of mutations aligned to published databases. In conclusion, we have developed an analytically-validated panel for application to cancers of disparate types with utility in liquid biopsy.
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2019 |
Huckins LM, Dobbyn A, Ruderfer DM, Hoffman G, Wang W, Pardinas AF, et al., 'Gene expression imputation across multiple brain regions provides insights into schizophrenia risk (vol 51, pg 659, 2019)', NATURE GENETICS, 51 1068-1068 (2019)
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2019 |
Li A, Geyer FC, Blecua P, Lee JY, Selenica P, Brown DN, et al., 'Homologous recombination DNA repair defects in PALB2-associated breast cancers (vol 5, 23, 2019)', NPJ BREAST CANCER, 5 (2019)
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2019 |
Pouget JG, Schizophrenia Working Group of the Psychiatric Genomics Consortium, Han B, Wu Y, Mignot E, Ollila HM, et al., 'Cross-disorder analysis of schizophrenia and 19 immune-mediated diseases identifies shared genetic risk.', Human molecular genetics, 28 3498-3513 (2019) [C1]
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Nova |
2019 |
Xavier A, Scott RJ, Talseth-Palmer BA, 'TAPES: A tool for assessment and prioritisation in exome studies', PLoS Computational Biology, 15 (2019) [C1]
Next-generation sequencing continues to grow in importance for researchers. Exome sequencing became a widespread tool to further study the genomic basis of Mendelian diseases. In ... [more]
Next-generation sequencing continues to grow in importance for researchers. Exome sequencing became a widespread tool to further study the genomic basis of Mendelian diseases. In an effort to identify pathogenic variants, reject benign variants and better predict variant effects in downstream analysis, the American College of Medical Genetics (ACMG) published a set of criteria in 2015. While there are multiple publicly available software's available to assign the ACMG criteria, most of them do not take into account multi-sample variant calling formats. Here we present a tool for assessment and prioritisation in exome studies (TAPES, https://github.com/a-xavier/tapes), an open-source tool designed for small-scale exome studies. TAPES can quickly assign ACMG criteria using ANNOVAR or VEP annotated files and implements a model to transform the categorical ACMG criteria into a continuous probability, allowing for a more accurate classification of pathogenicity or benignity of variants. In addition, TAPES can work with cohorts sharing a common phenotype by utilising a simple enrichment analysis, requiring no controls as an input as well as providing powerful filtering and reporting options. Finally, benchmarks showed that TAPES outperforms available tools to detect both pathogenic and benign variants, while also integrating the identification of enriched variants in study cohorts compared to the general population, making it an ideal tool to evaluate a smaller cohort before using bigger scale studies.
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Nova |
2019 |
Seppala TT, Ahadova A, Dominguez-Valentin M, Macrae F, Evans DG, Therkildsen C, et al., 'Lack of association between screening interval and cancer stage in Lynch syndrome may be accounted for by over-diagnosis; a prospective Lynch syndrome database report', HEREDITARY CANCER IN CLINICAL PRACTICE, 17 (2019) [C1]
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Nova |
2019 |
Butel-Simoes GI, Spigelman AD, Scott RJ, Vilain RE, 'Low-level parental mosaicism in an apparent de novo case of Peutz Jeghers syndrome', Familial Cancer, 18 109-112 (2019) [C1]
We report the case of a female found to have mosaicism for mutation in the STK11 gene, with the mutant allele expressed in her gametes, evident by her affected offspring, and in h... [more]
We report the case of a female found to have mosaicism for mutation in the STK11 gene, with the mutant allele expressed in her gametes, evident by her affected offspring, and in her gastrointestinal tract demonstrated on an excised polyp analysed for diagnosis. Mosaicism for Peutz¿Jeghers syndrome (PJS) has been reported in a small number of cases previously but a clinical presentation such as this has not previously been described. This finding of mosaicism was several years after initial investigations failed to identify the same STK11 mutation in this woman whose son was diagnosed with PJS at a young age. This case highlights the importance of considering mosaicism as an explanation for apparent de novo cases of PJS syndrome. It also has implications for genetic counselling, predictive testing and cancer screening.
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Nova |
2019 |
Harold D, Connolly S, Riley BP, Kendler KS, McCarthy SE, McCombie WR, et al., 'Population-based identity-by-descent mapping combined with exome sequencing to detect rare risk variants for schizophrenia', American Journal of Medical Genetics, Part B: Neuropsychiatric Genetics, 180 223-231 (2019) [C1]
Genome-wide association studies (GWASs) are highly effective at identifying common risk variants for schizophrenia. Rare risk variants are also important contributors to schizophr... [more]
Genome-wide association studies (GWASs) are highly effective at identifying common risk variants for schizophrenia. Rare risk variants are also important contributors to schizophrenia etiology but, with the exception of large copy number variants, are difficult to detect with GWAS. Exome and genome sequencing, which have accelerated the study of rare variants, are expensive so alternative methods are needed to aid detection of rare variants. Here we re-analyze an Irish schizophrenia GWAS dataset (n = 3,473) by performing identity-by-descent (IBD) mapping followed by exome sequencing of individuals identified as sharing risk haplotypes to search for rare risk variants in coding regions. We identified 45 rare haplotypes (>1 cM) that were significantly more common in cases than controls. By exome sequencing 105 haplotype carriers, we investigated these haplotypes for functional coding variants that could be tested for association in independent GWAS samples. We identified one rare missense variant in PCNT but did not find statistical support for an association with schizophrenia in a replication analysis. However, IBD mapping can prioritize both individual samples and genomic regions for follow-up analysis but genome rather than exome sequencing may be more effective at detecting risk variants on rare haplotypes.
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Nova |
2019 |
Hu¨bel C, Gaspar HA, Coleman JRI, Hanscombe KB, Purves K, Prokopenko I, et al., 'Genetic correlations of psychiatric traits with body composition and glycemic traits are sex- and age-dependent', Nature Communications, 10 [C1]
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2019 |
van Erp TGM, Walton E, Hibar DP, Schmaal L, Jiang W, Glahn DC, et al., 'Reply to: New Meta- and Mega-analyses of Magnetic Resonance Imaging Findings in Schizophrenia: Do They Really Increase Our Knowledge About the Nature of the Disease Process?', BIOLOGICAL PSYCHIATRY, 85 E35-E39 (2019)
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2019 |
Dbniak T, Scott RJ, Lea RA, Górski B, Masoj B, Cybulski C, et al., 'Founder mutations for early onset melanoma as revealed by whole exome sequencing suggests that this is not associated with the increasing incidence of melanoma in Poland', Cancer Research and Treatment, 51 337-344 (2019) [C1]
Purpose: Germline mutations within melanoma susceptibility genes are present only in minority of melanoma patients and it is expected that additional genes will be discovered with... [more]
Purpose: Germline mutations within melanoma susceptibility genes are present only in minority of melanoma patients and it is expected that additional genes will be discovered with next generation sequence technology and whole-exome sequencing (WES). Materials and Methods: Herein we performed WES on a cohort of 96 unrelated Polish patients with melanoma diagnosed under the age of 40 years who all screened negative for the presence of CDKN2A-variants. A replication study using a set of 1,200 melanoma patient DNA samples and similarly large series of healthy controls was undertaken. Results: We selected 21 potentially deleterious variants in 20 genes (VRK1, MYCT1, DNAH14, CASC3, MS4A12, PRC1, WWOX, CARD6, EXO5, CASC3, CASP8AP2, STK33, SAMD11, CNDP2, CPNE1, EFCAB6, CABLES1, LEKR1, NUDT17, and RRP15), which were identified by WES and confirmed by Sanger sequencing for an association study. Evaluation of the allele distribution among carriers and their relatives in available family trios revealed that these variants were unlikely to account for many familial cases of melanoma. Replication study revealed no statistically significant differences between cases and controls. Conclusion: Although most of the changes seemed to be neutral we could not exclude an association between variants in VRK1, CREB3L3, EXO5, and STK33 with melanoma risk.
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Nova |
2019 |
Zhang X, Morten BC, Scott RJ, Avery-Kiejda KA, 'A Simple Migration/Invasion Workflow Using an Automated Live-cell Imager', JOVE-JOURNAL OF VISUALIZED EXPERIMENTS, (2019) [C1]
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Nova |
2019 |
Tan AG, Kifley A, Flood VM, Holliday EG, Scott RJ, Cumming RG, et al., 'Evaluating the associations between obesity and age-related cataract: A Mendelian randomization study', American Journal of Clinical Nutrition, 110 969-976 (2019) [C1]
Background: The obesity-cataract association has been inconsistently reported. The fat mass and obesity-related (FTO) single-nucleotide polymorphism (SNP) rs9939609 is a major SNP... [more]
Background: The obesity-cataract association has been inconsistently reported. The fat mass and obesity-related (FTO) single-nucleotide polymorphism (SNP) rs9939609 is a major SNP associated with obesity and has been used as an instrumental variable for obesity in a Mendelian randomization (MR) approach. An interaction between the FTO SNP and macronutrient intake for obesity was suggested previously. Objective: The aim of this study was to assess the associations between obesity and cataract, using FTO SNP rs9939609 as an instrumental variable in an MR approach, and explore interactions of this SNP with macronutrient intake in relation to risk of cataract in a population-based cohort. Methods: The Blue Mountains Eye Study (BMES) is a longitudinal population-based study of common eye disease. Of 3654 baseline participants of the BMES (1992-1994), 2334 (75.8% of survivors) and 1952 (76.7% of survivors) were followed 5 and 10 y later. During the 5-y follow-up, 1174 new participants were examined. Cumulative cataract was defined as the presence of cortical, nuclear, or posterior subcapsular (PSC) cataract at any visit, following the Wisconsin Cataract Grading System. Imputed dosage of the FTO SNP rs9939609 was used. Quintiles of macronutrient intake (carbohydrates, protein, fats) were derived from an FFQ. ORs and 95% CIs were estimated using multivariable-adjusted logistic regression models. Results: After multivariable adjustment, there were no associations between BMI and any cataract types in MR models using rs9939609 as an instrumental variable. However, an interaction between rs9939609 and protein intake for PSC cataract risk was suggested (P = 0.03). In analyses stratified by quintiles of protein intake, each minor allele of rs9939609 was associated with increased odds of PSC (OR: 2.14; 95% CI: 1.27, 3.60) in the lowest quintile subgroup only. Conclusions: Obesity was not causally associated with age-related cataract. However, among persons in the lowest quintile of protein intake, obesity may be associated with PSC cataract.
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Nova |
2019 |
Pietrzak S, Wójcik J, Scott RJ, Kashyap A, Grodzki T, Baszuk P, et al., 'Influence of the selenium level on overall survival in lung cancer', Journal of Trace Elements in Medicine and Biology, 56 46-51 (2019) [C1]
Background: Although the results of studies in populations with low selenium status indicate an inverse correlation between body selenium levels and the risk of the lung cancer, t... [more]
Background: Although the results of studies in populations with low selenium status indicate an inverse correlation between body selenium levels and the risk of the lung cancer, the effect of this microelement on survival has not been studied. Materials and Methods: We performed a prospective study of 302 patients diagnosed with lung cancer in Szczecin, Poland. Selenium concentration in serum was measured at the time of diagnosis and before treatment. All patients were followed for a maximum of 80 months or until death. Vital status was obtained from the Polish National Death Registry. Results: Using Cox proportional hazard analysis, performed for all individuals with lung cancer, the hazard ratio (HR) for death from all causes was 1.25 (95% CI: 0.86¿1.83, P = 0.99) for patients in the lowest tertile compared to those in the highest tertile of serum selenium levels. Among the patients with stage I disease this relationship was significant (HR-2.73; P = 0.01) for selenium level in tertile 1 (<57 µg/L) compared to tertile 3 (>69 µg/L, reference). The 80 months crude survival after diagnosis was 79.5% (95% CI: 68.5¿92.4%) for individuals in the highest tertile and 58.1% (95% CI: 45.1¿74.9%) for individuals in the lowest tertile with stage I lung cancer. Conclusion: These results suggest that in patients undergoing treatment for stage I lung cancer, serum selenium levels at the time of diagnosis (>69 µg/L) may be associated with improved overall survival.
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Nova |
2019 |
Berry NK, Scott RJ, Rowlings P, Enjeti AK, 'Clinical use of SNP-microarrays for the detection of genome-wide changes in haematological malignancies', Critical Reviews in Oncology/Hematology, 142 58-67 (2019) [C1]
Single nucleotide polymorphism (SNP) microarrays are commonly used for the clinical investigation of constitutional genomic disorders; however, their adoption for investigating so... [more]
Single nucleotide polymorphism (SNP) microarrays are commonly used for the clinical investigation of constitutional genomic disorders; however, their adoption for investigating somatic changes is being recognised. With increasing importance being placed on defining the cancer genome, a shift in technology is imperative at a clinical level. Microarray platforms have the potential to become frontline testing, replacing or complementing standard investigations such as FISH or karyotype. This ¿molecular karyotype approach¿ exemplified by SNP-microarrays has distinct advantages in the investigation of several haematological malignancies. A growing body of literature, including guidelines, has shown support for the use of SNP-microarrays in the clinical laboratory to aid in a more accurate definition of the cancer genome. Understanding the benefits of this technology along with discussing the barriers to its implementation is necessary for the development and incorporation of SNP-microarrays in a clinical laboratory for the investigation of haematological malignancies.
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Nova |
2019 |
Schmidt AF, Holmes MV, Preiss D, Swerdlow DI, Denaxas S, Fatemifar G, et al., 'Phenome-wide association analysis of LDL-cholesterol lowering genetic variants in
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Nova |
2019 |
Yari H, Jin L, Teng L, Wang Y, Wu Y, Liu GZ, et al., 'LncRNA REG1CP promotes tumorigenesis through an enhancer complex to recruit FANCJ helicase for REG3A transcription', NATURE COMMUNICATIONS, 10 (2019) [C1]
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2019 |
Gill D, James NE, Monori G, Lorentzen E, Fernandez-Cadenas I, Lemmens R, et al., 'Genetically Determined Risk of Depression and Functional Outcome after Ischemic Stroke: Mendelian Randomization Study', Stroke, 50 2219-2222 (2019) [C1]
Background and Purpose-Psychosocial factors can have implications for ischemic stroke risk and recovery. This study investigated the effect of genetically determined risk of depre... [more]
Background and Purpose-Psychosocial factors can have implications for ischemic stroke risk and recovery. This study investigated the effect of genetically determined risk of depression on these outcomes using the Mendelian randomization (MR) framework. Methods-Genetic instruments for risk of depression were identified in a discovery genome-wide association study of 246 363 cases and 561 190 controls and further replicated in a separate population of 474 574 cases and 1 032 579 controls. Corresponding genetic association estimates for risk of ischemic stroke were taken from 60 341 cases and 454 450 controls, with those for functional outcome 3 months after ischemic stroke taken from an analysis of 6021 patients. Following statistical power calculation, inverse-variance weighted MR was performed to pool estimates across different instruments. The Cochran Q heterogeneity test, weighted median MR, and MR pleiotropy residual sum and outlier were used to explore possible bias relating to inclusion of pleiotropic variants. Results-There was no MR evidence for an effect of genetically determined risk of depression on ischemic stroke risk. Although suffering low statistical power, the main inverse-variance weighted MR analysis was suggestive of a detrimental effect of genetically determined risk of depression on functional outcome after ischemic stroke (odds ratio of poor outcome [modified Rankin Scale, =3] per 1-SD increase in genetically determined risk of depression, 1.81; 95% CI, 0.98-3.35; P=0.06). There was no evidence of heterogeneity between MR estimates produced by different instruments (Q P=0.26). Comparable MR estimates were obtained with weighted median MR (odds ratio, 2.57; 95% CI, 1.05-6.25; P=0.04) and MR pleiotropy residual sum and outlier (odds ratio, 1.81; 95% CI, 0.95-3.46; P=0.08). Conclusions-We found no MR evidence of genetically determined risk of depression affecting ischemic stroke risk but did find consistent MR evidence suggestive of a possible effect on functional outcome after ischemic stroke. Given the widespread prevalence of depression-related morbidity, these findings could have implications for prognostication and personalized rehabilitation after stroke.
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2019 |
Mavaddat N, Michailidou K, Dennis J, Lush M, Fachal L, Lee A, et al., 'Polygenic Risk Scores for Prediction of Breast Cancer and Breast Cancer Subtypes', American Journal of Human Genetics, 104 21-34 (2019) [C1]
Stratification of women according to their risk of breast cancer based on polygenic risk scores (PRSs) could improve screening and prevention strategies. Our aim was to develop PR... [more]
Stratification of women according to their risk of breast cancer based on polygenic risk scores (PRSs) could improve screening and prevention strategies. Our aim was to develop PRSs, optimized for prediction of estrogen receptor (ER)-specific disease, from the largest available genome-wide association dataset and to empirically validate the PRSs in prospective studies. The development dataset comprised 94,075 case subjects and 75,017 control subjects of European ancestry from 69 studies, divided into training and validation sets. Samples were genotyped using genome-wide arrays, and single-nucleotide polymorphisms (SNPs) were selected by stepwise regression or lasso penalized regression. The best performing PRSs were validated in an independent test set comprising 11,428 case subjects and 18,323 control subjects from 10 prospective studies and 190,040 women from UK Biobank (3,215 incident breast cancers). For the best PRSs (313 SNPs), the odds ratio for overall disease per 1 standard deviation in ten prospective studies was 1.61 (95%CI: 1.57¿1.65) with area under receiver-operator curve (AUC) = 0.630 (95%CI: 0.628¿0.651). The lifetime risk of overall breast cancer in the top centile of the PRSs was 32.6%. Compared with women in the middle quintile, those in the highest 1% of risk had 4.37- and 2.78-fold risks, and those in the lowest 1% of risk had 0.16- and 0.27-fold risks, of developing ER-positive and ER-negative disease, respectively. Goodness-of-fit tests indicated that this PRS was well calibrated and predicts disease risk accurately in the tails of the distribution. This PRS is a powerful and reliable predictor of breast cancer risk that may improve breast cancer prevention programs.
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2019 |
Karlsson Linnér R, Biroli P, Kong E, Meddens SFW, Wedow R, Fontana MA, et al., 'Genome-wide association analyses of risk tolerance and risky behaviors in over 1 million individuals identify hundreds of loci and shared genetic influences', Nature Genetics, 51 245-257 (2019) [C1]
Humans vary substantially in their willingness to take risks. In a combined sample of over 1 million individuals, we conducted genome-wide association studies (GWAS) of general ri... [more]
Humans vary substantially in their willingness to take risks. In a combined sample of over 1 million individuals, we conducted genome-wide association studies (GWAS) of general risk tolerance, adventurousness, and risky behaviors in the driving, drinking, smoking, and sexual domains. Across all GWAS, we identified hundreds of associated loci, including 99 loci associated with general risk tolerance. We report evidence of substantial shared genetic influences across risk tolerance and the risky behaviors: 46 of the 99 general risk tolerance loci contain a lead SNP for at least one of our other GWAS, and general risk tolerance is genetically correlated (|r^ g| ~ 0.25 to 0.50) with a range of risky behaviors. Bioinformatics analyses imply that genes near SNPs associated with general risk tolerance are highly expressed in brain tissues and point to a role for glutamatergic and GABAergic neurotransmission. We found no evidence of enrichment for genes previously hypothesized to relate to risk tolerance.
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2019 |
Sukiennicki GM, Marciniak W, Muszynska M, Baszuk P, Gupta S, Bialkowska K, et al., 'Iron levels, genes involved in iron metabolism and antioxidative processes and lung cancer incidence', PLOS ONE, 14 (2019) [C1]
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Nova |
2019 |
Söderholm M, Pedersen A, Lorentzen E, Stanne TM, Bevan S, Olsson M, et al., 'Genome-wide association meta-analysis of functional outcome after ischemic stroke', Neurology, 92 E1271-E1283 (2019) [C1]
ObjectiveTo discover common genetic variants associated with poststroke outcomes using a genome-wide association (GWA) study.MethodsThe study comprised 6,165 patients with ischemi... [more]
ObjectiveTo discover common genetic variants associated with poststroke outcomes using a genome-wide association (GWA) study.MethodsThe study comprised 6,165 patients with ischemic stroke from 12 studies in Europe, the United States, and Australia included in the GISCOME (Genetics of Ischaemic Stroke Functional Outcome) network. The primary outcome was modified Rankin Scale score after 60 to 190 days, evaluated as 2 dichotomous variables (0-2 vs 3-6 and 0-1 vs 2-6) and subsequently as an ordinal variable. GWA analyses were performed in each study independently and results were meta-analyzed. Analyses were adjusted for age, sex, stroke severity (baseline NIH Stroke Scale score), and ancestry. The significance level was p < 5 × 10-8.ResultsWe identified one genetic variant associated with functional outcome with genome-wide significance (modified Rankin Scale scores 0-2 vs 3-6, p = 5.3 × 10-9). This intronic variant (rs1842681) in the LOC105372028 gene is a previously reported trans-Expression quantitative trait locus for PPP1R21, which encodes a regulatory subunit of protein phosphatase 1. This ubiquitous phosphatase is implicated in brain functions such as brain plasticity. Several variants detected in this study demonstrated suggestive association with outcome (p < 10-5), some of which are within or near genes with experimental evidence of influence on ischemic stroke volume and/or brain recovery (e.g., NTN4, TEK, and PTCH1).ConclusionsIn this large GWA study on functional outcome after ischemic stroke, we report one significant variant and several variants with suggestive association to outcome 3 months after stroke onset with plausible mechanistic links to poststroke recovery. Future replication studies and exploration of potential functional mechanisms for identified genetic variants are warranted.
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Nova |
2019 |
Dork T, Peterlongo P, Mannermaa A, Bolla MK, Wang Q, Dennis J, et al., 'Two truncating variants in
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Nova |
2019 |
Petit J, Carroll G, Gould T, Pockney P, Dun M, Scott RJ, 'Cell-free DNA as a Diagnostic Blood-Based Biomarker for Colorectal Cancer: A Systematic Review', Journal of Surgical Research, 236 184-197 (2019) [C1]
Background: Circulating tumour DNA (ctDNA) has emerged as an excellent candidate for the future of liquid biopsies for many cancers. There has been growing interest in blood-based... [more]
Background: Circulating tumour DNA (ctDNA) has emerged as an excellent candidate for the future of liquid biopsies for many cancers. There has been growing interest in blood-based liquid biopsy because of the potential of ctDNA to produce a noninvasive test that can be used for: the diagnosis of colorectal cancer, monitoring therapy response, and providing information on overall prognosis. The aim of this review was to collate and explore the current evidence regarding ctDNA as a screening tool for colorectal cancer (CRC). Methods: A systematic review of published articles in English over the past 20 y was performed using Medline, Embase, and Cochrane databases on May 23, 2017. After a full-text review, a total of 69 studies were included. Two assessment tools were used to review and compare the methodological quality of these studies. Results: Among the 69 studies included, 17 studies reviewed total cfDNA, whereas six studies looked at the DNA integrity index and 15 focused on ctDNA. There were a total of 40 studies that reviewed methylated cfDNA with 19 of these focussing specifically on SEPT9. Conclusions: The results of this review indicate that methylated epigenetic ctDNA markers are perhaps the most promising candidates for a blood-based CRC-screening modality using cell-free (cf) DNA. Methylated cfDNA appears to be less specific for CRC compared to ctDNA; however, they have demonstrated good sensitivity for early-stage CRC. Further research is required to determine which methylated cfDNA markers are the most accurate when applied to large cohorts of patients. In addition, reliable comparison of results across multiple studies would benefit from standardization of methodology for DNA extraction and PCR techniques in the future.
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2019 |
Dominguez-Valentin M, Seppälä TT, Sampson JR, Macrae F, Winship I, Evans DG, et al., 'Survival by colon cancer stage and screening interval in Lynch syndrome: a prospective Lynch syndrome database report.', Hered Cancer Clin Pract, 17 28 (2019) [C1]
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2019 |
Li A, Geyer FC, Blecua P, Lee JY, Selenica P, Brown DN, et al., 'Homologous recombination DNA repair defects in
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Nova |
2019 |
Xavier MJ, Nixon B, Roman SD, Scott RJ, Drevet JR, Aitken RJ, 'Paternal impacts on development: Identification of genomic regions vulnerable to oxidative DNA damage in human spermatozoa', Human Reproduction, 34 1876-1890 (2019) [C1]
STUDY QUESTION: Do all regions of the paternal genome within the gamete display equivalent vulnerability to oxidative DNA damage? SUMMARY ANSWER: Oxidative DNA damage is not rando... [more]
STUDY QUESTION: Do all regions of the paternal genome within the gamete display equivalent vulnerability to oxidative DNA damage? SUMMARY ANSWER: Oxidative DNA damage is not randomly distributed in mature human spermatozoa but is instead targeted, with particular chromosomes being especially vulnerable to oxidative stress. WHAT IS KNOWN ALREADY: Oxidative DNA damage is frequently encountered in the spermatozoa of male infertility patients. Such lesions can influence the incidence of de novo mutations in children, yet it remains to be established whether all regions of the sperm genome display equivalent susceptibility to attack by reactive oxygen species. STUDY DESIGN, SIZE, DURATION: Human spermatozoa obtained from normozoospermic males (n = 8) were split into equivalent samples and subjected to either hydrogen peroxide (H2O2) treatment or vehicle controls before extraction of oxidized DNA using a modified DNA immunoprecipitation (MoDIP) protocol. Specific regions of the genome susceptible to oxidative damage were identified by next-generation sequencing and validated in the spermatozoa of normozoospermic males (n = 18) and in patients undergoing infertility evaluation (n = 14). PARTICIPANTS/MATERIALS, SETTING, METHODS: Human spermatozoa were obtained from normozoospermic males and divided into two identical samples prior to being incubated with either H2O2 (5 mm, 1 h) to elicit oxidative stress or an equal volume of vehicle (untreated controls). Alternatively, spermatozoa were obtained from fertility patients assessed as having high basal levels of oxidative stress within their spermatozoa. All semen samples were subjected to MoDIP to selectively isolate oxidized DNA, prior to sequencing of the resultant DNA fragments using a next-generation whole-genomic sequencing platform. Bioinformatic analysis was then employed to identify genomic regions vulnerable to oxidative damage, several of which were selected for real-time quantitative PCR (qPCR) validation. MAIN RESULTS AND THE ROLE OF CHANCE: Approximately 9000 genomic regions, 150-1000 bp in size, were identified as highly vulnerable to oxidative damage in human spermatozoa. Specific chromosomes showed differential susceptibility to damage, with chromosome 15 being particularly sensitive to oxidative attack while the sex chromosomes were protected. Susceptible regions generally lay outside protamine-and histone-packaged domains. Furthermore, we confirmed that these susceptible genomic sites experienced a dramatic (2-15-fold) increase in their burden of oxidative DNA damage in patients undergoing infertility evaluation compared to normal healthy donors. LIMITATIONS, REASONS FOR CAUTION: The limited number of samples analysed in this study warrants external validation, as do the implications of our findings. Selection of male fertility patients was based on high basal levels of oxidative stress within their spermatozoa as opposed to specific sub-classes of male factor infertility. WIDER IMPLICATIONS OF THE FINDINGS: The identification of genomic regions susceptible to oxidation in the male germ line will be of value in focusing future analyses into the mutational load carried by children in response to paternal factors such as age, the treatment of male infertility using ART and paternal exposure to environmental toxicants. STUDY FUNDING/COMPETING INTEREST(S): Project support was provided by the University of Newcastle's (UoN) Priority Research Centre for Reproductive Science. M.J.X. was a recipient of a UoN International Postgraduate Research Scholarship. B.N. is the recipient of a National Health and Medical Research Council of Australia Senior Research Fellowship. Authors declare no conflict of interest.
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Nova |
2019 |
Figlioli G, Bogliolo M, Catucci I, Caleca L, Viz Lasheras S, Pujol R, et al., 'The
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2018 |
Bialkowska K, Marciniak W, Muszynska M, Baszuk P, Gupta S, Jaworska-Bieniek K, et al., 'Association of zinc level and polymorphism in MMP-7 gene with prostate cancer in Polish population', PLOS ONE, 13 (2018) [C1]
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Nova |
2018 |
Debniak T, Scott RJ, Górski B, Masojc B, Kram A, Maleszka R, et al., 'BRCA1/2 mutations are not a common cause of malignant melanoma in the Polish population', PloS one, 13 (2018) [C1]
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Nova |
2018 |
Kamien B, Ronan A, Poke G, Sinnerbrink I, Baynam G, Ward M, et al., 'A Clinical Review of Generalized Overgrowth Syndromes in the Era of Massively Parallel Sequencing', Molecular Syndromology, 9 70-82 (2018) [C1]
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Nova |
2018 |
Xavier MJ, Mitchell LA, McEwan KE, Scott RJ, Aitken RJ, 'Genomic integrity in the male germ line: evidence in support of the disposable soma hypothesis.', Reproduction, 156 269-282 (2018) [C1]
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Nova |
2018 |
Evangelou E, Warren HR, Mosen-Ansorena D, Mifsud B, Pazoki R, Gao H, et al., 'Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits (vol 50, pg 1412, 2018)', NATURE GENETICS, 50 1755-1755 (2018)
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2018 |
O'Mara TA, Glubb DM, Amant F, Annibali D, Ashton K, Attia J, et al., 'Identification of nine new susceptibility loci for endometrial cancer', NATURE COMMUNICATIONS, 9 (2018) [C1]
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Nova |
2018 |
LeBlanc M, Zuber V, Thompson WK, Andreassen OA, Frigessi A, Andreassen BK, 'A correction for sample overlap in genome-wide association studies in a polygenic pleiotropy-informed framework', BMC GENOMICS, 19 (2018)
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Nova |
2018 |
Ni G, Gratten J, Wray NR, Lee SH, Ripke S, Neale BM, et al., 'Age at first birth in women is genetically associated with increased risk of schizophrenia', Scientific Reports, 8 (2018) [C1]
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Nova |
2018 |
Lee JJ, Wedow R, Okbay A, Kong E, Maghzian O, Zacher M, et al., 'Gene discovery and polygenic prediction from a genome-wide association study of educational attainment in 1.1 million individuals', Nature Genetics, 50 1112-1121 (2018) [C1]
Here we conducted a large-scale genetic association analysis of educational attainment in a sample of approximately 1.1 million individuals and identify 1,271 independent genome-w... [more]
Here we conducted a large-scale genetic association analysis of educational attainment in a sample of approximately 1.1 million individuals and identify 1,271 independent genome-wide-significant SNPs. For the SNPs taken together, we found evidence of heterogeneous effects across environments. The SNPs implicate genes involved in brain-development processes and neuron-to-neuron communication. In a separate analysis of the X chromosome, we identify 10 independent genome-wide-significant SNPs and estimate a SNP heritability of around 0.3% in both men and women, consistent with partial dosage compensation. A joint (multi-phenotype) analysis of educational attainment and three related cognitive phenotypes generates polygenic scores that explain 11¿13% of the variance in educational attainment and 7¿10% of the variance in cognitive performance. This prediction accuracy substantially increases the utility of polygenic scores as tools in research.
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Nova |
2018 |
Kennedy DW, White NM, Benton MC, Fox A, Scott RJ, Griffiths LR, et al., 'Critical evaluation of linear regression models for cell-subtype specific methylation signal from mixed blood cell DNA', PLOS ONE, 13 (2018) [C1]
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Nova |
2018 |
Kelly S, Jahanshad N, Zalesky A, Kochunov P, Agartz I, Alloza C, et al., 'Widespread white matter microstructural differences in schizophrenia across 4322 individuals: results from the ENIGMA Schizophrenia DTI Working Group.', Molecular psychiatry, 23 1261-1269 (2018) [C1]
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Nova |
2018 |
Fullerton JM, Klauser P, Lenroot RK, Shaw AD, Overs B, Heath A, et al., 'Differential effect of disease-associated
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Nova |
2018 |
Groen K, Lea RA, Maltby VE, Scott RJ, Lechner-Scott J, 'Letter to the editor: blood processing and sample storage have negligible effects on methylation', CLINICAL EPIGENETICS, 10 (2018) [C1]
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Nova |
2018 |
Joo JE, Dowty JG, Milne RL, Wong EM, Dugue P-A, English D, et al., 'Heritable DNA methylation marks associated with susceptibility to breast cancer', NATURE COMMUNICATIONS, 9 (2018)
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2018 |
Ko YA, Jamaluddin MFB, Adebayo M, Bajwa P, Scott RJ, Dharmarajan AM, et al., 'Extracellular matrix (ECM) activates ß-catenin signaling in uterine fibroids', Reproduction, 155 61-71 (2018) [C1]
Recent studies showed that genetic aberrations in the MED12 gene, probably through the canonical WNT/ß-catenin pathway, lead to the pathogenesis of uterine fibroids. However, a co... [more]
Recent studies showed that genetic aberrations in the MED12 gene, probably through the canonical WNT/ß-catenin pathway, lead to the pathogenesis of uterine fibroids. However, a comprehensive analysis of the WNT pathway in MED12-mutated and MED12-wildtype fibroids has not been performed. The objective of this study was to determine the status of the WNT pathway in human fibroids. We performed Sanger sequencing to define the MED12 mutational status of fibroids and normal myometrium samples. qPCR arrays were carried out to determine the status of the WNT signaling pathway in MED12-mutated and MED12-wild-type fibroids. Liquid chromatography-mass spectrometry (LC-MS), Western blotting and immunohistochemistry were used to monitor the expression of ß-catenin. We showed that ß-catenin expression was increased in fibroids compared to the adjacent myometrium samples. However, ß-catenin expression showed no correlation with MED12 mutation status. Of all the WNT signaling components, WNT inhibitors showed the greatest differences in expression between fibroids and controls. WIF1, a WNT inhibitor, was identified as the most significantly upregulated gene in fibroids. We cultured primary fibroid cells on hydrogels of known stiffness to decipher the influence of biomechanical cues on ß-catenin expression and revealed increased levels of ß-catenin when cells were cultured on a stiffer surface. In conclusion, our data showed that ß-catenin expression in fibroids occurs independently of MED12 mutations. Biomechanical changes upregulate ß-catenin expression in fibroids, providing an attractive avenue for developing new treatments for this disease.
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Nova |
2018 |
Cox AJ, Zhang P, Evans TJ, Scott RJ, Cripps AW, West NP, 'Gene expression profiles in whole blood and associations with metabolic dysregulation in obesity', Obesity Research and Clinical Practice, 12 204-213 (2018) [C1]
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Nova |
2018 |
Maltby VE, Lea RA, Graves MC, Sanders KA, Benton MC, Tajouri L, et al., 'Genome-wide DNA methylation changes in CD19+ B cells from relapsing-remitting multiple sclerosis patients.', Scientific reports, 8 (2018) [C1]
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Nova |
2018 |
van Erp TGM, Walton E, Hibar DP, Schmaal L, Jiang W, Glahn DC, et al., 'Cortical Brain Abnormalities in 4474 Individuals With Schizophrenia and 5098 Control Subjects via the Enhancing Neuro Imaging Genetics Through Meta Analysis (ENIGMA) Consortium', Biological Psychiatry, 84 644-654 (2018) [C1]
Background: The profile of cortical neuroanatomical abnormalities in schizophrenia is not fully understood, despite hundreds of published structural brain imaging studies. This st... [more]
Background: The profile of cortical neuroanatomical abnormalities in schizophrenia is not fully understood, despite hundreds of published structural brain imaging studies. This study presents the first meta-analysis of cortical thickness and surface area abnormalities in schizophrenia conducted by the ENIGMA (Enhancing Neuro Imaging Genetics through Meta Analysis) Schizophrenia Working Group. Methods: The study included data from 4474 individuals with schizophrenia (mean age, 32.3 years; range, 11¿78 years; 66% male) and 5098 healthy volunteers (mean age, 32.8 years; range, 10¿87 years; 53% male) assessed with standardized methods at 39 centers worldwide. Results: Compared with healthy volunteers, individuals with schizophrenia have widespread thinner cortex (left/right hemisphere: Cohen's d = -0.530/-0.516) and smaller surface area (left/right hemisphere: Cohen's d = -0.251/-0.254), with the largest effect sizes for both in frontal and temporal lobe regions. Regional group differences in cortical thickness remained significant when statistically controlling for global cortical thickness, suggesting regional specificity. In contrast, effects for cortical surface area appear global. Case-control, negative, cortical thickness effect sizes were two to three times larger in individuals receiving antipsychotic medication relative to unmedicated individuals. Negative correlations between age and bilateral temporal pole thickness were stronger in individuals with schizophrenia than in healthy volunteers. Regional cortical thickness showed significant negative correlations with normalized medication dose, symptom severity, and duration of illness and positive correlations with age at onset. Conclusions: The findings indicate that the ENIGMA meta-analysis approach can achieve robust findings in clinical neuroscience studies; also, medication effects should be taken into account in future genetic association studies of cortical thickness in schizophrenia.
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Nova |
2018 |
Ibn Sina AA, Carrascosa LG, Liang Z, Grewal YS, Wardiana A, Shiddiky MJA, et al., 'Epigenetically reprogrammed methylation landscape drives the DNA self-assembly and serves as a universal cancer biomarker', NATURE COMMUNICATIONS, 9 (2018) [C1]
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Nova |
2018 |
Ligthart S, Vaez A, Võsa U, Stathopoulou MG, de Vries PS, Prins BP, et al., 'Genome Analyses of >200,000 Individuals Identify 58 Loci for Chronic Inflammation and Highlight Pathways that Link Inflammation and Complex Disorders', American Journal of Human Genetics, 103 691-706 (2018) [C1]
C-reactive protein (CRP) is a sensitive biomarker of chronic low-grade inflammation and is associated with multiple complex diseases. The genetic determinants of chronic inflammat... [more]
C-reactive protein (CRP) is a sensitive biomarker of chronic low-grade inflammation and is associated with multiple complex diseases. The genetic determinants of chronic inflammation remain largely unknown, and the causal role of CRP in several clinical outcomes is debated. We performed two genome-wide association studies (GWASs), on HapMap and 1000 Genomes imputed data, of circulating amounts of CRP by using data from 88 studies comprising 204,402 European individuals. Additionally, we performed in silico functional analyses and Mendelian randomization analyses with several clinical outcomes. The GWAS meta-analyses of CRP revealed 58 distinct genetic loci (p < 5 × 10-8). After adjustment for body mass index in the regression analysis, the associations at all except three loci remained. The lead variants at the distinct loci explained up to 7.0% of the variance in circulating amounts of CRP. We identified 66 gene sets that were organized in two substantially correlated clusters, one mainly composed of immune pathways and the other characterized by metabolic pathways in the liver. Mendelian randomization analyses revealed a causal protective effect of CRP on schizophrenia and a risk-increasing effect on bipolar disorder. Our findings provide further insights into the biology of inflammation and could lead to interventions for treating inflammation and its clinical consequences.
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2018 |
Rhead B, Brorson IS, Berge T, Adams C, Quach H, Moen SM, et al., 'Increased DNA methylation of
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2018 |
Painter JN, O'Mara TA, Morris AP, Cheng THT, Gorman M, Martin L, et al., 'Genetic overlap between endometriosis and endometrial cancer: Evidence from cross-disease genetic correlation and GWAS meta-analyses', Cancer Medicine, 5 1978-1987 (2018) [C1]
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Nova |
2018 |
Scott RJ, Willink PW, Norton BM, 'Biogeography and Distribution of the Cryptic Species Rosyface Shiner
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2018 |
Revelas M, Thalamuthu A, Oldmeadow C, Evans TJ, Armstrong NJ, Kwok JB, et al., 'Review and meta-analysis of genetic polymorphisms associated with exceptional human longevity', Mechanisms of Ageing and Development, 175 24-34 (2018) [C1]
Background: Many factors contribute to exceptional longevity, with genetics playing a significant role. However, to date, genetic studies examining exceptional longevity have been... [more]
Background: Many factors contribute to exceptional longevity, with genetics playing a significant role. However, to date, genetic studies examining exceptional longevity have been inconclusive. This comprehensive review seeks to determine the genetic variants associated with exceptional longevity by undertaking meta-analyses. Methods: Meta-analyses of genetic polymorphisms previously associated with exceptional longevity (85+) were undertaken. For each variant, meta-analyses were performed if there were data from at least three independent studies available, including two unpublished additional cohorts. Results: Five polymorphisms, ACE rs4340, APOE e2/3/4, FOXO3A rs2802292, KLOTHO KL-VS and IL6 rs1800795 were significantly associated with exceptional longevity, with the pooled effect sizes (odds ratios) ranging from 0.42 (APOE e4) to 1.45 (FOXO3A males). Conclusion: In general, the observed modest effect sizes of the significant variants suggest many genes of small influence play a role in exceptional longevity, which is consistent with results for other polygenic traits. Our results also suggest that genes related to cardiovascular health may be implicated in exceptional longevity. Future studies should examine the roles of gender and ethnicity and carefully consider study design, including the selection of appropriate controls.
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2018 |
Li N, Rowley SM, Goode DL, Amarasinghe KC, McInerny S, Devereux L, et al., 'Mutations in
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2018 |
Abdullah N, Murad NAA, Attia J, Oldmeadow C, Kamaruddin MA, Jalal NA, et al., 'Differing contributions of classical risk factors to type 2 diabetes in multi-ethnic Malaysian populations', International Journal of Environmental Research and Public Health, 15 (2018) [C1]
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2018 |
Anttila V, Bulik-Sullivan B, Finucane HK, Walters RK, Bras J, Duncan L, et al., 'Analysis of shared heritability in common disorders of the brain', Science, 360 (2018) [C1]
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2018 |
Ten Broeke SW, van der Klift HM, Tops CMJ, Aretz S, Bernstein I, Buchanan DD, et al., 'Cancer Risks for PMS2-Associated Lynch Syndrome.', Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 36 2961-2968 (2018) [C1]
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2018 |
Davies G, Lam M, Harris SE, Trampush JW, Luciano M, Hill WD, et al., 'Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function', NATURE COMMUNICATIONS, 9 (2018) [C1]
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Nova |
2018 |
Evangelou E, Warren HR, Mosen-Ansorena D, Mifsud B, Pazoki R, Gao H, et al., 'Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits', Nature Genetics, 50 1412-1425 (2018) [C1]
High blood pressure is a highly heritable and modifiable risk factor for cardiovascular disease. We report the largest genetic association study of blood pressure traits (systolic... [more]
High blood pressure is a highly heritable and modifiable risk factor for cardiovascular disease. We report the largest genetic association study of blood pressure traits (systolic, diastolic and pulse pressure) to date in over 1 million people of European ancestry. We identify 535 novel blood pressure loci that not only offer new biological insights into blood pressure regulation but also highlight shared genetic architecture between blood pressure and lifestyle exposures. Our findings identify new biological pathways for blood pressure regulation with potential for improved cardiovascular disease prevention in the future.
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2018 |
Chatterjee G, Pai T, Hardiman T, Avery-Kiejda K, Scott RJ, Spencer J, et al., 'Molecular patterns of cancer colonisation in lymph nodes of breast cancer patients', Breast cancer research : BCR, 20 (2018) [C1]
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2018 |
Ruderfer DM, Ripke S, McQuillin A, Boocock J, Stahl EA, Pavlides JMW, et al., 'Genomic Dissection of Bipolar Disorder and Schizophrenia, Including 28 Subphenotypes', Cell, 173 1705-1715.e16 (2018) [C1]
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2018 |
Wu L, Shi W, Long J, Guo X, Michailidou K, Beesley J, et al., 'A transcriptome-wide association study of 229,000 women identifies new candidate susceptibility genes for breast cancer', Nature Genetics, 50 968-978 (2018) [C1]
The breast cancer risk variants identified in genome-wide association studies explain only a small fraction of the familial relative risk, and the genes responsible for these asso... [more]
The breast cancer risk variants identified in genome-wide association studies explain only a small fraction of the familial relative risk, and the genes responsible for these associations remain largely unknown. To identify novel risk loci and likely causal genes, we performed a transcriptome-wide association study evaluating associations of genetically predicted gene expression with breast cancer risk in 122,977 cases and 105,974 controls of European ancestry. We used data from the Genotype-Tissue Expression Project to establish genetic models to predict gene expression in breast tissue and evaluated model performance using data from The Cancer Genome Atlas. Of the 8,597 genes evaluated, significant associations were identified for 48 at a Bonferroni-corrected threshold of P < 5.82 × 10 -6 , including 14 genes at loci not yet reported for breast cancer. We silenced 13 genes and showed an effect for 11 on cell proliferation and/or colony-forming efficiency. Our study provides new insights into breast cancer genetics and biology.
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2018 |
Groen K, Maltby VE, Lea RA, Sanders KA, Fink JL, Scott RJ, et al., 'Erythrocyte microRNA sequencing reveals differential expression in relapsing-remitting multiple sclerosis.', BMC medical genomics, 11 (2018) [C1]
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Nova |
2018 |
Iglesias AI, Mishra A, Vitart V, Bykhovskaya Y, Höhn R, Springelkamp H, et al., 'Cross-ancestry genome-wide association analysis of corneal thickness strengthens link between complex and Mendelian eye diseases', Nature Communications, 9 (2018) [C1]
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Nova |
2018 |
Holmes M, Connor T, Oldmeadow C, Pockney PG, Scott RJ, Talseth-Palmer BA, 'CD36-a plausible modifier of disease phenotype in familial adenomatous polyposis', HEREDITARY CANCER IN CLINICAL PRACTICE, 16 (2018) [C1]
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Nova |
2018 |
Maltby VE, Lea RA, Ribbons KA, Sanders KA, Kennedy D, Min M, et al., 'DNA methylation changes in CD4+ T cells isolated from multiple sclerosis patients on dimethyl fumarate.', Multiple Sclerosis Journal - Experimental, Translational and Clinical, 4 (2018) [C1]
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Nova |
2018 |
Jamaluddin MFB, Ko YA, Kumar M, Brown Y, Bajwa P, Nagendra PB, et al., 'Proteomic profiling of human uterine fibroids reveals upregulation of the extracellular matrix protein periostin', Endocrinology, 159 1106-1118 (2018) [C1]
The central characteristic of uterine fibroids is excessive deposition of extracellular matrix (ECM), which contributes to fibroid growth and bulk-type symptoms. Despite this, ver... [more]
The central characteristic of uterine fibroids is excessive deposition of extracellular matrix (ECM), which contributes to fibroid growth and bulk-type symptoms. Despite this, very little is known about patterns of ECM protein expression in fibroids and whether these are influenced by the most common genetic anomalies, which relate to MED12. We performed extensive genetic and proteomic analyses of clinically annotated fibroids and adjacent normal myometrium to identify the composition and expression patterns of ECM proteins in MED12 mutation-positive and mutation-negative uterine fibroids. Genetic sequencing of tissue samples revealed MED12 alterations in 39 of 65 fibroids (60%) from 14 patients. Using isobaric tagged-based quantitative mass spectrometry on three selected patients (n = 9 fibroids), we observed a common set of upregulated (.1.5-fold) and downregulated (,0.66-fold) proteins in small, medium, and large fibroid samples of annotated MED12 status. These two sets of upregulated and downregulated proteins were the same in all patients, regardless of variations in fibroid size and MED12 status. We then focused on one of the significant upregulated ECM proteins and confirmed the differential expression of periostin using western blotting and immunohistochemical analysis. Our study defined the proteome of uterine fibroids and identified that increased ECM protein expression, in particular periostin, is a hallmark of uterine fibroids regardless of MED12 mutation status. This study sets the foundation for further investigations to analyze the mechanisms regulating ECM overexpression and the functional role of upregulated ECM proteins in leiomyogenesis.
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Nova |
2018 |
Ni G, Moser G, Ripke S, Neale BM, Corvin A, Walters JTR, et al., 'Estimation of Genetic Correlation via Linkage Disequilibrium Score Regression and Genomic Restricted Maximum Likelihood', American Journal of Human Genetics, 102 1185-1194 (2018) [C1]
Genetic correlation is a key population parameter that describes the shared genetic architecture of complex traits and diseases. It can be estimated by current state-of-art method... [more]
Genetic correlation is a key population parameter that describes the shared genetic architecture of complex traits and diseases. It can be estimated by current state-of-art methods, i.e., linkage disequilibrium score regression (LDSC) and genomic restricted maximum likelihood (GREML). The massively reduced computing burden of LDSC compared to GREML makes it an attractive tool, although the accuracy (i.e., magnitude of standard errors) of LDSC estimates has not been thoroughly studied. In simulation, we show that the accuracy of GREML is generally higher than that of LDSC. When there is genetic heterogeneity between the actual sample and reference data from which LD scores are estimated, the accuracy of LDSC decreases further. In real data analyses estimating the genetic correlation between schizophrenia (SCZ) and body mass index, we show that GREML estimates based on ~150,000 individuals give a higher accuracy than LDSC estimates based on ~400,000 individuals (from combined meta-data). A GREML genomic partitioning analysis reveals that the genetic correlation between SCZ and height is significantly negative for regulatory regions, which whole genome or LDSC approach has less power to detect. We conclude that LDSC estimates should be carefully interpreted as there can be uncertainty about homogeneity among combined meta-datasets. We suggest that any interesting findings from massive LDSC analysis for a large number of complex traits should be followed up, where possible, with more detailed analyses with GREML methods, even if sample sizes are lesser.
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Nova |
2018 |
Wyss AB, Sofer T, Lee MK, Terzikhan N, Nguyen JN, Lahousse L, et al., 'Multiethnic meta-analysis identifies ancestry-specific and cross-ancestry loci for pulmonary function', Nature Communications, 9 (2018) [C1]
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Nova |
2017 |
Pan X, Bowman M, Scott RJ, Fitter J, Smith R, Zakar T, 'Promoter methylation pattern controls corticotropin releasing hormone gene activity in human trophoblasts', PLoS ONE, 12 1-18 (2017) [C1]
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Nova |
2017 |
Daneshi N, Holliday E, Hancock S, Schneider JJ, Scott RJ, Attia J, Milward EA, 'Prevalence of clinically actionable genotypes and medication exposure of older adults in the community', Pharmacogenomics and Personalized Medicine, 10 17-27 (2017) [C1]
This study analyzed clinically actionable pharmacogenotypes for clopidogrel, warfarin, statins, thiopurines, and tacrolimus using microarray data for 2121 participants (55¿85 year... [more]
This study analyzed clinically actionable pharmacogenotypes for clopidogrel, warfarin, statins, thiopurines, and tacrolimus using microarray data for 2121 participants (55¿85 years) from the Australian Hunter Community Study (HCS). At least 74% of participants (95% confidence interval [CI]: 72%¿76%) had strong level evidence for at least one medium- or high-risk actionable genotype that would trigger a change in standard therapy under current international recommendations. About 14% of these participants (95% CI: 12%¿16%) were taking medication potentially affected by the genotype in question. Furthermore, ~2.6% of all participants with medication data (95% CI: 1.4%¿3.8%) had a high-risk clinically actionable genotype for a medication to which they were exposed. This represents a considerable number of people at the population level. Although relationships between genotype and health outcomes remain contentious, pharmacogenotyping of multiple variants simultaneously may have considerable potential to improve medication safety and efficacy for older people in the community.
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Nova |
2017 |
Strumidlo A, Skiba S, Scott RJ, Lubinski J, 'The potential role of miRNAs in therapy of breast and ovarian cancers associated with BRCA1 mutation', Hereditary Cancer in Clinical Practice, 15 1-5 (2017) [C1]
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Nova |
2017 |
Le Hellard S, Wang Y, Witoelar A, Zuber V, Bettella F, Hugdahl K, et al., 'Identification of Gene Loci That Overlap Between Schizophrenia and Educational Attainment', Schizophrenia Bulletin, 43 654-664 (2017) [C1]
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Nova |
2017 |
Burnard S, Lechner-Scott J, Scott RJ, 'EBV and MS: Major cause, minor contribution or red-herring?', Multiple Sclerosis and Related Disorders, 16 24-30 (2017) [C1]
Multiple Sclerosis (MS) is a chronic neurological disease with genetic and environmental risk factors. Epstein Barr-Virus (EBV) has been closely associated with MS but with a sign... [more]
Multiple Sclerosis (MS) is a chronic neurological disease with genetic and environmental risk factors. Epstein Barr-Virus (EBV) has been closely associated with MS but with a significant amount of conflicting evidence. Some of the evidence for EBV involvement in MS includes: almost 100% of MS patients showing past EBV infection, an association with Infectious Mononucleosis (acute EBV infection), higher titres of EBV antibodies associated with an increased risk of MS development, and an overall altered immune response to EBV found in peripheral blood and the CNS of MS patients. However, evidence for EBV presence in the CSF and T cell responses to EBV in MS have been particularly conflicting. Several hypotheses have been proposed for direct and indirect EBV involvement in MS such as 1) Molecular Mimicry 2) Mistaken Self 3) Bystander Damage and 4) Autoreactive B cells infected with EBV. More recently, an association between EBV and human endogenous retrovirus in MS has been shown, which may provide an alternative pathogenetic target for MS treatment. However, if EBV is not the major contributor to MS and is instead one of several viral or infectious agents able to elicit a similar altered immune response, MS development may be the result of a failure of viral clearance in general. This review aims to evaluate the evidence for the currently discussed theories of EBV involvement in MS pathogenesis.
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Nova |
2017 |
Hansen MF, Johansen J, Sylvander AE, Bjørnevoll I, Talseth-Palmer BA, Lavik LAS, et al., 'Use of multigene-panel identifies pathogenic variants in several CRC-predisposing genes in patients previously tested for Lynch Syndrome', Clinical Genetics, 92 405-414 (2017) [C1]
Background: Many families with a high burden of colorectal cancer fulfil the clinical criteria for Lynch Syndrome. However, in about half of these families, no germline mutation i... [more]
Background: Many families with a high burden of colorectal cancer fulfil the clinical criteria for Lynch Syndrome. However, in about half of these families, no germline mutation in the mismatch repair genes known to be associated with this disease can be identified. The aim of this study was to find the genetic cause for the increased colorectal cancer risk in these unsolved cases. Materials and methods: To reach the aim, we designed a gene panel targeting 112 previously known or candidate colorectal cancer susceptibility genes to screen 274 patient samples for mutations. Mutations were validated by Sanger sequencing and, where possible, segregation analysis was performed. Results: We identified 73 interesting variants, of whom 17 were pathogenic and 19 were variants of unknown clinical significance in well-established cancer susceptibility genes. In addition, 37 potentially pathogenic variants in candidate colorectal cancer susceptibility genes were detected. Conclusion: In conclusion, we found a promising DNA variant in more than 25 % of the patients, which shows that gene panel testing is a more effective method to identify germline variants in CRC patients compared to a single gene approach.
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Nova |
2017 |
Atkinson RJ, Fulham WR, Michie PT, Ward PB, Todd J, Stain H, et al., 'Electrophysiological, cognitive and clinical profiles of at-risk mental state: The longitudinal Minds in Transition (MinT) study', PLOS ONE, 12 (2017) [C1]
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Nova |
2017 |
Gorski M, Van der Most PJ, Teumer A, Chu AY, Li M, Mijatovic V, et al., '1000 Genomes-based meta-analysis identifies 10 novel loci for kidney function', SCIENTIFIC REPORTS, 7 (2017) [C1]
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Nova |
2017 |
Gromowski T, Gapska P, Scott RJ, Kaklewski K, Marciniak W, Durda K, et al., 'Serum 25(OH)D concentration, common variants of the VDR gene and lung cancer occurrence', International Journal of Cancer, 141 336-341 (2017) [C1]
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Nova |
2017 |
Avery-Kiejda KA, Mathe A, Scott RJ, 'Genome-wide miRNA, gene and methylation analysis of triple negative breast cancer to identify changes associated with lymph node metastases', Genomics Data, 14 1-4 (2017) [C1]
Triple negative breast cancer (TNBC) is a particularly important breast cancer subtype with an aggressive clinical phenotype that is associated with a higher likelihood of metasta... [more]
Triple negative breast cancer (TNBC) is a particularly important breast cancer subtype with an aggressive clinical phenotype that is associated with a higher likelihood of metastasis. This subtype is characterized by an absence of the estrogen (ER) and progesterone (PR) receptors, as well as the human epidermal growth factor receptor 2 (HER2/HER neu). The absence of the three receptors significantly reduces targeted treatment options for patients with TNBC and as such, there is an urgent need to identify novel treatment targets. Here, we provide detailed information regarding the design of a multi-platform dataset that describes genome-wide assessment of miRNA (assessed by microarray, GSE38167) and gene expression (assessed by microarray, GSE61723), as well as methylation (assessed by Illumina HM450K BeadChip, GSE78751) in TNBCs, matched normal adjacent tissues and matched lymph node metastases. The use of this multi-platform dataset is likely to uncover novel markers and key pathways involved in progression to lymph node metastasis in TNBC.
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Nova |
2017 |
Najdawi F, Crook A, Maidens J, McEvoy C, Fellowes A, Pickett J, et al., 'Lessons learnt from implementation of a Lynch syndrome screening program for patients with gynaecological malignancy', Pathology, 49 457-464 (2017) [C1]
Despite a trend towards universal testing, best practice to screen patients presenting with gynaecological malignancy for Lynch syndrome (LS) is uncertain. We report our instituti... [more]
Despite a trend towards universal testing, best practice to screen patients presenting with gynaecological malignancy for Lynch syndrome (LS) is uncertain. We report our institutional experience of a co-ordinated gynaecological LS screening program. All patients with endometrial carcinoma or carcinosarcoma, or gynaecological endometrioid or clear cell carcinomas undergo reflex four panel immunohistochemistry (IHC) for MLH1, PMS2, MSH2 and MSH6 followed by cascade somatic hypermethylation analysis of the MLH1 promoter locus for dual MLH1/PMS2 negative tumours. On the basis of these results, genetic counselling and targeted germline mutation testing is then offered to patients considered at high risk of LS. From 1 August 2013 to 31 December 2015, 124 patients were screened (mean age 64.6 years). Thirty-six (29.0%) demonstrated abnormal MMR IHC: 26 (72.2%) showed dual loss of MLH1/PMS2, five (13.9%) dual loss of MSH2/MSH6, three (8.3%) isolated loss of MSH6, and two (5.6%) isolated loss of PMS2. Twenty-five of 26 (96.1%) patients with dual MLH1/PMS2 loss demonstrated MLH1 promoter methylation. Therefore, 11 (8.9%) patients screened were classified as high risk for LS, of whom nine (81.8%) accepted germline mutation testing. Three (2.4% of total screened) were confirmed to have LS, two with germline PMS2 and one with germline MSH2 mutation. Massive parallel sequencing of tumour tissue demonstrated somatic mutations which were concordant with the IHC results in the remainder. Interestingly, the one MLH1/PMS2 IHC negative but not hypermethylated tumour harboured only somatic MLH1 mutations, indicating that universal cascade methylation testing in MLH1/PMS2 IHC negative tumours is very low yield and could be reconsidered in a resource-poor setting. In conclusion, universal screening for LS in patients presenting with gynaecological malignancy using the algorithm described above identified LS in three of 124 (2.4%) of our population. Only three of nine (33.3%) patients considered at high risk for LS by combined IHC and hypermethylation analysis were proven to have LS. Only one of the LS patients was less than 50 years of age and none of these patients would have been identified had more restrictive Amsterdam or Bethesda criteria been applied.
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Nova |
2017 |
Maltby VE, Lea RA, Sanders KA, White N, Benton MC, Scott RJ, Lechner-Scott J, 'Differential methylation at MHC in CD4
Background: Although many genetic variants have been associated with multiple sclerosis (MS) risk, they do not explain all the disease risk and there remains uncertainty as to how... [more]
Background: Although many genetic variants have been associated with multiple sclerosis (MS) risk, they do not explain all the disease risk and there remains uncertainty as to how these variants contribute to disease. DNA methylation is an epigenetic mechanism that can influence gene expression and has the potential to mediate the effects of environmental factors on MS. In a previous study, we found a differentially methylation region (DMR) at MHC HLA-DRB1 that was associated within relapsing-remitting MS (RRMS) patients in CD4+ T cells. This study aimed to confirm this earlier finding in an independent RRMS cohort of treatment-naive female patients. Methods: Total genomic DNA was extracted from CD4+ T cells of 28 female RRMS and 22 age-matched healthy controls subjects. DNA was bisulfite-converted and hybridised to Illumina 450K arrays. Beta values for all CpGs were analysed using the DMPFinder function in the MINFI program, and a follow-up prioritisation process was applied to identify the most robust MS-associated DMRs. Results: This study confirmed our previous findings of a hypomethylated DMR at HLA-DRB1 and a hypermethylated DMR at HLA-DRB5 in this RRMS patient cohort. In addition, we identified a large independent DMR at MHC, whereby 11 CpGs in RNF39 were hypermethylated in MS cases compared to controls (max. ¿beta = 0.19, P = 2.1 × 10-4). We did not find evidence that SNP genotype was influencing the DMR in this cohort. A smaller MHC DMR was also identified at HCG4B, and two non-MHC DMRs at PM20D1 on chr1 and ERICH1 on chr8 were also identified. Conclusions: The findings from this study confirm our previous results of a DMR at HLA-DRB1 and also suggest hypermethylation in an independent MHC locus, RNF39, is associated with MS. Taken together, our results highlight the importance of epigenetic factors at the MHC locus in MS independent of treatment, age and sex. Prospective studies are now required to discern whether methylation at MHC is involved in influencing risk of disease onset or whether the disease itself has altered the methylation profile.
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Nova |
2017 |
Schmiegel W, Scott RJ, Dooley S, Lewis W, Meldrum CJ, Pockney P, et al., 'Blood-based detection of
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Nova |
2017 |
de Vries PS, Sabater-Lleal M, Chasman DI, Trompet S, Ahluwalia TS, Teumer A, et al., 'Comparison of HapMap and 1000 Genomes Reference Panels in a Large-Scale Genome-Wide Association Study', PLOS ONE, 12 (2017) [C1]
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Nova |
2017 |
Marshall CR, Howrigan DP, Merico D, Thiruvahindrapuram B, Wu W, Greer DS, et al., 'Contribution of copy number variants to schizophrenia from a genome-wide study of 41,321 subjects', Nature Genetics, 49 27-35 (2017) [C1]
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Nova |
2017 |
Scott RJ, 'The PerformanceStat Potential: A Leadership Strategy for Producing Results', AUSTRALIAN JOURNAL OF PUBLIC ADMINISTRATION, 76 268-270 (2017)
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2017 |
Naudin C, Smith B, Bond DR, Dun MD, Scott RJ, Ashman LK, et al., 'Characterization of the early molecular changes in the glomeruli of Cd151 -/- mice highlights induction of mindin and MMP-10.', Scientific Reports, 7 15987-15987 (2017) [C1]
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Nova |
2017 |
Maguire JM, Bevan S, Stanne TM, Lorenzen E, Fernandez-Cadenas I, Hankey GJ, et al., 'GISCOME - Genetics of Ischaemic Stroke Functional Outcome network: A protocol for an international multicentre genetic association study', EUROPEAN STROKE JOURNAL, 2 229-237 (2017)
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2017 |
Smith-Anttila CJA, Bensing S, Alimohammadi M, Dalin F, Oscarson M, Zhang MD, et al., 'Identification of endothelin-converting enzyme-2 as an autoantigen in autoimmune polyendocrine syndrome type 1', Autoimmunity, 50 223-231 (2017) [C1]
Autoimmune polyendocrine syndrome type 1 (APS1) is a rare monogenic autoimmune disorder caused by mutations in the autoimmune regulator (AIRE) gene. High titer autoantibodies are ... [more]
Autoimmune polyendocrine syndrome type 1 (APS1) is a rare monogenic autoimmune disorder caused by mutations in the autoimmune regulator (AIRE) gene. High titer autoantibodies are a characteristic feature of APS1 and are often associated with particular disease manifestations. Pituitary deficits are reported in up to 7% of all APS1 patients, with immunoreactivity to pituitary tissue frequently reported. We aimed to isolate and identify specific pituitary autoantigens in patients with APS1. Immunoscreening of a pituitary cDNA expression library identified endothelin-converting enzyme (ECE)-2 as a potential candidate autoantigen. Immunoreactivity against ECE-2 was detected in 46% APS1 patient sera, with no immunoreactivity detectable in patients with other autoimmune disorders or healthy controls. Quantitative-PCR showed ECE-2 mRNA to be most abundantly expressed in the pancreas with high levels also in the pituitary and brain. In the pancreas ECE-2 was co-expressed with insulin or somatostatin, but not glucagon and was widely expressed in GH producing cells in the guinea pig pituitary. The correlation between immunoreactivity against ECE-2 and the major recognized clinical phenotypes of APS1 including hypopituitarism was not apparent. Our results identify ECE-2 as a specific autoantigen in APS1 with a restricted neuroendocrine distribution.
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Nova |
2017 |
Biswas M, Dias TH, Daneshi N, Holliday E, Hancock S, Attia J, et al., 'Potential simple and multifactorial drug-gene interactions of tricyclic antidepressantsin older Australians', GSTF Journal of Advances in Medical Research, 2 (2017) [C1]
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Nova |
2017 |
Wain LV, Vaez A, Jansen R, Joehanes R, Van Der Most PJ, Erzurumluoglu AM, et al., 'Novel Blood Pressure Locus and Gene Discovery Using Genome-Wide Association Study and Expression Data Sets from Blood and the Kidney', Hypertension, 70 e4-e19 (2017) [C1]
Elevated blood pressure is a major risk factor for cardiovascular disease and has a substantial genetic contribution. Genetic variation influencing blood pressure has the potentia... [more]
Elevated blood pressure is a major risk factor for cardiovascular disease and has a substantial genetic contribution. Genetic variation influencing blood pressure has the potential to identify new pharmacological targets for the treatment of hypertension. To discover additional novel blood pressure loci, we used 1000 Genomes Project-based imputation in 150 134 European ancestry individuals and sought significant evidence for independent replication in a further 228 245 individuals. We report 6 new signals of association in or near HSPB7, TNXB, LRP12, LOC283335, SEPT9, and AKT2, and provide new replication evidence for a further 2 signals in EBF2 and NFKBIA. Combining large whole-blood gene expression resources totaling 12 607 individuals, we investigated all novel and previously reported signals and identified 48 genes with evidence for involvement in blood pressure regulation that are significant in multiple resources. Three novel kidney-specific signals were also detected. These robustly implicated genes may provide new leads for therapeutic innovation.
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Nova |
2017 |
Warren HR, Evangelou E, Cabrera CP, Gao H, Ren M, Mifsud B, et al., 'Genome-wide association analysis identifies novel blood pressure loci and offers biological insights into cardiovascular risk', Nature Genetics, 49 403-415 (2017) [C1]
Elevated blood pressure is the leading heritable risk factor for cardiovascular disease worldwide. We report genetic association of blood pressure (systolic, diastolic, pulse pres... [more]
Elevated blood pressure is the leading heritable risk factor for cardiovascular disease worldwide. We report genetic association of blood pressure (systolic, diastolic, pulse pressure) among UK Biobank participants of European ancestry with independent replication in other cohorts, and robust validation of 107 independent loci. We also identify new independent variants at 11 previously reported blood pressure loci. In combination with results from a range of in silico functional analyses and wet bench experiments, our findings highlight new biological pathways for blood pressure regulation enriched for genes expressed in vascular tissues and identify potential therapeutic targets for hypertension. Results from genetic risk score models raise the possibility of a precision medicine approach through early lifestyle intervention to offset the impact of blood pressure-raising genetic variants on future cardiovascular disease risk.
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Nova |
2017 |
Milne RL, Kuchenbaecker KB, Michailidou K, Beesley J, Kar S, Lindström S, et al., 'Identification of ten variants associated with risk of estrogen-receptor-negative breast cancer', Nature Genetics, 49 1767-1778 (2017) [C1]
Most common breast cancer susceptibility variants have been identified through genome-wide association studies (GWAS) of predominantly estrogen receptor (ER)-positive disease1. We... [more]
Most common breast cancer susceptibility variants have been identified through genome-wide association studies (GWAS) of predominantly estrogen receptor (ER)-positive disease1. We conducted a GWAS using 21,468 ER-negative cases and 100,594 controls combined with 18,908 BRCA1 mutation carriers (9,414 with breast cancer), all of European origin. We identified independent associations at P < 5 × 10-8 with ten variants at nine new loci. At P < 0.05, we replicated associations with 10 of 11 variants previously reported in ER-negative disease or BRCA1 mutation carrier GWAS and observed consistent associations with ER-negative disease for 105 susceptibility variants identified by other studies. These 125 variants explain approximately 16% of the familial risk of this breast cancer subtype. There was high genetic correlation (0.72) between risk of ER-negative breast cancer and breast cancer risk for BRCA1 mutation carriers. These findings may lead to improved risk prediction and inform further fine-mapping and functional work to better understand the biological basis of ER-negative breast cancer.
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Nova |
2017 |
Delforce SJ, Lumbers ER, de Meaultsart CC, Wang Y, Proietto A, Otton G, et al., 'Expression of renin-angiotensin system (RAS) components in endometrial cancer', ENDOCRINE CONNECTIONS, 6 9-19 (2017) [C1]
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Nova |
2017 |
McLaughlin RL, Schijven D, Van Rheenen W, Van Eijk KR, O'Brien M, Kahn RS, et al., 'Genetic correlation between amyotrophic lateral sclerosis and schizophrenia', Nature Communications, 8 (2017) [C1]
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Nova |
2017 |
Gorski M, van der Most PJ, Teumer A, Chu AY, Li M, Mijatovic V, et al., '1000 Genomes-based meta-analysis identifies 10 novel loci for kidney function (vol 7, 45040, 2017)', SCIENTIFIC REPORTS, 7 (2017)
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2017 |
Fazekas-Lavu M, Parker A, Spigelman AD, Scott RJ, Epstein RJ, Jensen M, Samaras K, 'Thyroid cancer in a patient with Lynch syndrome - case report and literature review', THERAPEUTICS AND CLINICAL RISK MANAGEMENT, 13 915-918 (2017) [C1]
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Nova |
2017 |
Dymerska D, Golebiewska K, Kuswik M, Rudnicka H, Scott RJ, Billings R, et al., 'New EPCAM founder deletion in Polish population', Clinical Genetics, 92 649-653 (2017) [C1]
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Nova |
2017 |
Abdullah N, Abdul Murad NA, Mohd Haniff EA, Syafruddin SE, Attia J, Oldmeadow C, et al., 'Predicting type 2 diabetes using genetic and environmental risk factors in a multi-ethnic Malaysian cohort', Public Health, 149 31-38 (2017) [C1]
Objective Malaysia has a high and rising prevalence of type 2 diabetes (T2D). While environmental (non-genetic) risk factors for the disease are well established, the role of gene... [more]
Objective Malaysia has a high and rising prevalence of type 2 diabetes (T2D). While environmental (non-genetic) risk factors for the disease are well established, the role of genetic variations and gene¿environment interactions remain understudied in this population. This study aimed to estimate the relative contributions of environmental and genetic risk factors to T2D in Malaysia and also to assess evidence for gene¿environment interactions that may explain additional risk variation. Study design This was a case¿control study including 1604 Malays, 1654 Chinese and 1728 Indians from the Malaysian Cohort Project. Methods The proportion of T2D risk variance explained by known genetic and environmental factors was assessed by fitting multivariable logistic regression models and evaluating McFadden's pseudo R2 and the area under the receiver-operating characteristic curve (AUC). Models with and without the genetic risk score (GRS) were compared using the log likelihood ratio Chi-squared test and AUCs. Multiplicative interaction between genetic and environmental risk factors was assessed via logistic regression within and across ancestral groups. Interactions were assessed for the GRS and its 62 constituent variants. Results The models including environmental risk factors only had pseudo R2 values of 16.5¿28.3% and AUC of 0.75¿0.83. Incorporating a genetic score aggregating 62 T2D-associated risk variants significantly increased the model fit (likelihood ratio P-value of 2.50 × 10-4¿4.83 × 10-12) and increased the pseudo R2 by about 1¿2% and AUC by 1¿3%. None of the gene¿environment interactions reached significance after multiple testing adjustment, either for the GRS or individual variants. For individual variants, 33 out of 310 tested associations showed nominal statistical significance with 0.001 < P < 0.05. Conclusion This study suggests that known genetic risk variants contribute a significant but small amount to overall T2D risk variation in Malaysian population groups. If gene¿environment interactions involving common genetic variants exist, they are likely of small effect, requiring substantially larger samples for detection.
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Nova |
2017 |
Warren HR, Evangelou E, Cabrera CP, Gao H, Ren M, Mifsud B, et al., 'Genome-wide association analysis identifies novel blood pressure loci and offers biological insights into cardiovascular risk (vol 49, pg 403, 2017)', NATURE GENETICS, 49 1558-1558 (2017)
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2017 |
Michailidou K, Lindström S, Dennis J, Beesley J, Hui S, Kar S, et al., 'Association analysis identifies 65 new breast cancer risk loci', Nature, 551 92-94 (2017) [C1]
Breast cancer risk is influenced by rare coding variants in susceptibility genes, such as BRCA1, and many common, mostly non-coding variants. However, much of the genetic contribu... [more]
Breast cancer risk is influenced by rare coding variants in susceptibility genes, such as BRCA1, and many common, mostly non-coding variants. However, much of the genetic contribution to breast cancer risk remains unknown. Here we report the results of a genome-wide association study of breast cancer in 122,977 cases and 105,974 controls of European ancestry and 14,068 cases and 13,104 controls of East Asian ancestry. We identified 65 new loci that are associated with overall breast cancer risk at P < 5 × 10-8. The majority of credible risk single-nucleotide polymorphisms in these loci fall in distal regulatory elements, and by integrating in silico data to predict target genes in breast cells at each locus, we demonstrate a strong overlap between candidate target genes and somatic driver genes in breast tumours. We also find that heritability of breast cancer due to all single-nucleotide polymorphisms in regulatory features was 2-5-fold enriched relative to the genome-wide average, with strong enrichment for particular transcription factor binding sites. These results provide further insight into genetic susceptibility to breast cancer and will improve the use of genetic risk scores for individualized screening and prevention.
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Nova |
2017 |
Berry NK, Dixon-McIver A, Scott RJ, Rowlings P, Enjeti AK, 'Detection of complex genomic signatures associated with risk in plasma cell disorders.', Cancer genetics, 218-219 1-9 (2017) [C1]
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Nova |
2017 |
Mahurkar S, Moldovan M, Suppiah V, Sorosina M, Clarelli F, Liberatore G, et al., 'Response to interferon-beta treatment in multiple sclerosis patients: A genome-wide association study', Pharmacogenomics Journal, 17 312-318 (2017) [C1]
Up to 50% of multiple sclerosis (MS) patients do not respond to interferon-beta (IFN-ß) treatment and determination of response requires lengthy clinical follow-up of up to 2 year... [more]
Up to 50% of multiple sclerosis (MS) patients do not respond to interferon-beta (IFN-ß) treatment and determination of response requires lengthy clinical follow-up of up to 2 years. Response predictive genetic markers would significantly improve disease management. We aimed to identify IFN-ß treatment response genetic marker(s) by performing a two-stage genome-wide association study (GWAS). The GWAS was carried out using data from 151 Australian MS patients from the ANZgene/WTCCC2 MS susceptibility GWAS (responder (R)=51, intermediate responders=24 and non-responders (NR)=76). Of the single-nucleotide polymorphisms (SNP) that were validated in an independent group of 479 IFN-ß-treated MS patients from Australia, Spain and Italy (R=273 and NR=206), eight showed evidence of association with treatment response. Among the replicated associations, the strongest was observed for FHIT (Fragile Histidine Triad; combined P-value 6.74 × 106) and followed by variants in GAPVD1 (GTPase activating protein and VPS9 domains 1; combined P-value 5.83 × 10 5) and near ZNF697 (combined P-value 8.15 × 10 5).
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Nova |
2016 |
Kamien B, Dadd T, Buckman M, Ronan A, Dudding T, Meldrum C, et al., 'Somatic-Gonadal Mosaicism Causing Sotos Syndrome', AMERICAN JOURNAL OF MEDICAL GENETICS PART A, 170 3360-3362 (2016)
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2016 |
Chen MM, O'Mara TA, Thompson DJ, Painter JN, Attia J, Black A, et al., 'GWAS meta-analysis of 16 852 women identifies new susceptibility locus for endometrial cancer', HUMAN MOLECULAR GENETICS, 25 2612-2620 (2016) [C1]
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2016 |
Painter JN, O'Mara TA, Marquart L, Webb PM, Attia J, Medland SE, et al., 'Genetic risk score mendelian randomization shows that obesity measured as body mass index, but not waist:hip ratio, is causal for endometrial cancer', Cancer Epidemiology Biomarkers and Prevention, 25 1503-1510 (2016) [C1]
Background: The strongest known risk factor for endometrial cancer is obesity. To determine whether SNPs associated with increased body mass index (BMI) or waist-hip ratio (WHR) a... [more]
Background: The strongest known risk factor for endometrial cancer is obesity. To determine whether SNPs associated with increased body mass index (BMI) or waist-hip ratio (WHR) are associated with endometrial cancer risk, independent of measured BMI, we investigated relationships between 77 BMI and 47 WHR SNPs and endometrial cancer in 6,609 cases and 37,926 country-matched controls. Methods: Logistic regression analysis and fixed effects metaanalysis were used to test for associations between endometrial cancer risk and (i) individual BMI orWHRSNPs, (ii) a combined weighted genetic risk score (wGRS) for BMI or WHR. Causality of BMI for endometrial cancer was assessed using Mendelian randomization, with BMIwGRS as instrumental variable. Results: The BMIwGRS was significantly associated with endometrial cancer risk (P -= 3.4 × 10-17). Scaling the effect of the BMIwGRS on endometrial cancer risk by its effect on BMI, the endometrial cancer OR per 5 kg/m2 of genetically predicted BMI was 2.06 [95% confidence interval (CI), 1.89-2.21], larger than the observed effect of BMI on endometrial cancer risk (OR-=1.55; 95% CI, 1.44-1.68, per 5 kg/m2). The association attenuated but remained significant after adjusting for BMI (OR -= 1.22; 95% CI, 1.10-1.39; P -= 5.3 × 10-4). There was evidence of directional pleiotropy (P -= 1.5 × 10-4). BMI SNP rs2075650 was associated with endometrial cancer at study-wide significance (P < 4.0 × 10-4), independent of BMI. Endometrial cancer was not significantly associated with individual WHR SNPs or the WHRwGRS. Conclusions: BMI, but not WHR, is causally associated with endometrial cancer risk, with evidence that some BMI-associated SNPs alter endometrial cancer risk via mechanisms other than measurable BMI. Impact: The causal association between BMI SNPs and endometrial cancer has possible implications for endometrial cancer risk modeling.
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Okbay A, Baselmans BML, De Neve JE, Turley P, Nivard MG, Fontana MA, et al., 'Genetic variants associated with subjective well-being, depressive symptoms, and neuroticism identified through genome-wide analyses', Nature Genetics, 48 624-633 (2016) [C1]
Very few genetic variants have been associated with depression and neuroticism, likely because of limitations on sample size in previous studies. Subjective well-being, a phenotyp... [more]
Very few genetic variants have been associated with depression and neuroticism, likely because of limitations on sample size in previous studies. Subjective well-being, a phenotype that is genetically correlated with both of these traits, has not yet been studied with genome-wide data. We conducted genome-wide association studies of three phenotypes: subjective well-being (n = 298,420), depressive symptoms (n = 161,460), and neuroticism (n = 170,911). We identify 3 variants associated with subjective well-being, 2 variants associated with depressive symptoms, and 11 variants associated with neuroticism, including 2 inversion polymorphisms. The two loci associated with depressive symptoms replicate in an independent depression sample. Joint analyses that exploit the high genetic correlations between the phenotypes (P = 0.8) strengthen the overall credibility of the findings and allow us to identify additional variants. Across our phenotypes, loci regulating expression in central nervous system and adrenal or pancreas tissues are strongly enriched for association.
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2016 |
Cheng THT, Thompson DJ, O'Mara TA, Painter JN, Glubb DM, Flach S, et al., 'Five endometrial cancer risk loci identified through genome-wide association analysis', Nature Genetics, 48 667-674 (2016) [C1]
We conducted a meta-analysis of three endometrial cancer genome-wide association studies (GWAS) and two follow-up phases totaling 7,737 endometrial cancer cases and 37,144 control... [more]
We conducted a meta-analysis of three endometrial cancer genome-wide association studies (GWAS) and two follow-up phases totaling 7,737 endometrial cancer cases and 37,144 controls of European ancestry. Genome-wide imputation and meta-analysis identified five new risk loci of genome-wide significance at likely regulatory regions on chromosomes 13q22.1 (rs11841589, near KLF5), 6q22.31 (rs13328298, in LOC643623 and near HEY2 and NCOA7), 8q24.21 (rs4733613, telomeric to MYC), 15q15.1 (rs937213, in EIF2AK4, near BMF) and 14q32.33 (rs2498796, in AKT1, near SIVA1). We also found a second independent 8q24.21 signal (rs17232730). Functional studies of the 13q22.1 locus showed that rs9600103 (pairwise r 2 = 0.98 with rs11841589) is located in a region of active chromatin that interacts with the KLF5 promoter region. The rs9600103[T] allele that is protective in endometrial cancer suppressed gene expression in vitro, suggesting that regulation of the expression of KLF5, a gene linked to uterine development, is implicated in tumorigenesis. These findings provide enhanced insight into the genetic and biological basis of endometrial cancer.
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2016 |
Lener MR, Scott RJ, Kluzniak W, Baszuk P, Cybulski C, Wiechowska-Kozlowska A, et al., 'Do founder mutations characteristic of some cancer sites also predispose to pancreatic cancer?', International Journal of Cancer, 139 601-606 (2016) [C1]
Understanding of the etiology and risk of pancreatic cancer (PaCa) is still poorly understood. This study evaluated the prevalence of 10 Polish founder mutations in four genes amo... [more]
Understanding of the etiology and risk of pancreatic cancer (PaCa) is still poorly understood. This study evaluated the prevalence of 10 Polish founder mutations in four genes among PaCa patients and assessed their possible association with the risk of disease in Poland. In the study 383 PaCa patients and 4,000 control subjects were genotyped for founder mutations in: BRCA1 (5382insC, 4153delA, C61G), CHEK2 (1100delC, IVS2 + 1G > A, del5395, I157T), NBS1 (657del5) and PALB2 (509-510delGA, 172-175delTTGT). A statistically significant association between the 657del5 mutation and an increased risk of pancreatic cancer was observed for NBS1 gene. The Slavic NBS1 gene mutation (657delACAAA) was detected in 8 of 383 (2.09%) unselected cases compared with 22 of 4,000 (0.55%) controls (OR: 3.80, p = 0.002). The PALB2 509-510delGA and 172-175delTTGT mutations combined were seen in 2 (0.52%) unselected cases of PaCa and in 8 (0.20%) of 4,000 controls (OR: 2.61, p = 0.49). For BRCA1, the three mutations combined were detected in 4 of 383 (1.04%) PaCa patients and in 17 of 4,000 (0.42%) controls (OR: 2.46, p = 0.20). CHEK2 mutations were not associated with the risk of pancreatic cancer (OR: 1.11, p = 0.72). The founder mutation in NBS1 (657del5) was associated with an increased risk of PaCa in heterozygous carriers, indicating that this mutation appears to predispose to cancer of the pancreas. By identifying pancreatic cancer risk groups, founder mutation testing in Poland should be considered for people at risk for PaCa.
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2016 |
Purrington KS, Visscher DW, Wang C, Yannoukakos D, Hamann U, Nevanlinna H, et al., 'Genes associated with histopathologic features of triple negative breast tumors predict molecular subtypes', Breast Cancer Research and Treatment, 157 117-131 (2016) [C1]
Distinct subtypes of triple negative (TN) breast cancer have been identified by tumor expression profiling. However, little is known about the relationship between histopathologic... [more]
Distinct subtypes of triple negative (TN) breast cancer have been identified by tumor expression profiling. However, little is known about the relationship between histopathologic features of TN tumors, which reflect aspects of both tumor behavior and tumor microenvironment, and molecular TN subtypes. The histopathologic features of TN tumors were assessed by central review and 593 TN tumors were subjected to whole genome expression profiling using the Illumina Whole Genome DASL array. TN molecular subtypes were defined based on gene expression data associated with histopathologic features of TN tumors. Gene expression analysis yielded signatures for four TN subtypes (basal-like, androgen receptor positive, immune, and stromal) consistent with previous studies. Expression analysis also identified genes significantly associated with the 12 histological features of TN tumors. Development of signatures using these markers of histopathological features resulted in six distinct TN subtype signatures, including an additional basal-like and stromal signature. The additional basal-like subtype was distinguished by elevated expression of cell motility and glucose metabolism genes and reduced expression of immune signaling genes, whereas the additional stromal subtype was distinguished by elevated expression of immunomodulatory pathway genes. Histopathologic features that reflect heterogeneity in tumor architecture, cell structure, and tumor microenvironment are related to TN subtype. Accounting for histopathologic features in the development of gene expression signatures, six major subtypes of TN breast cancer were identified.
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2016 |
Hungate EA, Vora SR, Gamazon ER, Moriyama T, Best T, Hulur I, et al., 'A variant at 9p21.3 functionally implicates CDKN2B in paediatric B-cell precursor acute lymphoblastic leukaemia aetiology.', Nature communications, 7 10635 (2016) [C1]
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2016 |
Johnson EC, Bjelland DW, Howrigan DP, Abdellaoui A, Breen G, Borglum A, et al., 'No Reliable Association between Runs of Homozygosity and Schizophrenia in a Well-Powered Replication Study', PLOS Genetics, 12 e1006343-e1006343 [C1]
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2016 |
De Vries PS, Chasman DI, Sabater-Lleal M, Chen MH, Huffman JE, Steri M, et al., 'A meta-analysis of 120 246 individuals identifies 18 new loci for fibrinogen concentration', Human Molecular Genetics, 25 358-370 (2016) [C1]
Genome-wide association studies have previously identified 23 genetic loci associated with circulating fibrinogen concentration. These studies used HapMap imputation and did not e... [more]
Genome-wide association studies have previously identified 23 genetic loci associated with circulating fibrinogen concentration. These studies used HapMap imputation and did not examine the X-chromosome. 1000 Genomes imputation provides better coverage of uncommon variants, and includes indels.We conducted a genome-wide association analysis of 34 studies imputed to the 1000 Genomes Project reference panel and including ~120 000 participants of European ancestry (95 806 participants with data on the X-chromosome). Approximately 10.7 million single-nucleotide polymorphisms and 1.2 million indelswere examined.We identified 41 genome-wide significant fibrinogen loci; of which, 18were newly identified. Therewere no genome-wide significant signals on the X-chromosome. The lead variants of five significant loci were indels. We further identified six additional independent signals, including three rare variants, at two previously characterized loci: FGB and IRF1. Together the 41 loci explain 3% of the variance in plasma fibrinogen concentration.
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2016 |
Okbay A, Baselmans BML, De Neve J-E, Turley P, Nivard MG, Fontana MA, et al., 'Genetic variants associated with subjective well-being, depressive symptoms, and neuroticism identified through genome-wide analyses (vol 48, pg 624, 2016)', NATURE GENETICS, 48 970-970 (2016)
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2016 |
Okbay A, Baselmans BML, De Neve J-E, Turley P, Nivard MG, Fontana MA, et al., 'Genetic variants associated with subjective well-being, depressive symptoms, and neuroticism identified through genome-wide analyses (vol 48, pg 624, 2016)', NATURE GENETICS, 48 1591-1591 (2016)
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McKenzie R, Scott RJ, Otton G, Scurry J, 'Early changes of endometrial neoplasia revealed by loss of mismatch repair gene protein expression in a patient diagnosed with Lynch syndrome', PATHOLOGY, 48 78-80 (2016)
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Thompson ER, Rowley SM, Li N, McInerny S, Devereux L, Wong-Brown MW, et al., 'Panel testing for familial breast cancer: Calibrating the tension between research and clinical care', Journal of Clinical Oncology, 34 1455-1459 (2016) [C1]
Purpose Gene panel sequencing is revolutionizing germline risk assessment for hereditary breast cancer. Despite scant evidence supporting the role of many of these genes in breast... [more]
Purpose Gene panel sequencing is revolutionizing germline risk assessment for hereditary breast cancer. Despite scant evidence supporting the role of many of these genes in breast cancer predisposition, results are often reported to families as the definitive explanation for their family history. We assessed the frequency of mutations in 18 genes included in hereditary breast cancer panels among index cases from families with breast cancer and matched population controls. Patients and Methods Cases (n= 2,000) were predominantly breast cancer-affected women referredto specialized Familial Cancer Centers on the basis of a strong family history of breast cancer and BRCA1 and BRCA2 wild type. Controls (n = 1,997) were cancer-free women from the LifePool study. Sequencing data were filtered for known pathogenic or novel loss-of-function mutations. Results Excluding 19 mutations identified in BRCA1 and BRCA2 among the cases and controls, a total of 78 cases (3.9%) and 33 controls (1.6%) were found to carry potentially actionable mutations. A significant excess of mutations was only observed for PALB2 (26 cases, four controls) and TP53 (five cases, zero controls), whereas no mutations were identified in STK11. Among the remaining genes, loss-of function mutations were rare, with similar frequency between cases and controls. Conclusion The frequency ofmutations in most breast cancer panel genes among individuals selected for possible hereditary breast cancer is low and, in many cases, similar or even lower than that observed among cancer-free population controls. Although multigene panels can significantly aid in cancer risk management and expedite clinical translation of new genes, they equally have the potential to provide clinical misinformation and harm at the individual level if the data are not interpreted cautiously.
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2016 |
Binder MD, Fox AD, Merlo D, Johnson LJ, Giuffrida L, Calvert SE, et al., 'Common and Low Frequency Variants in MERTK Are Independently Associated with Multiple Sclerosis Susceptibility with Discordant Association Dependent upon HLA-DRB1*15:01 Status', PLoS Genetics, 12 (2016) [C1]
Multiple Sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system. The risk of developing MS is strongly influenced by genetic predisposition, ... [more]
Multiple Sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system. The risk of developing MS is strongly influenced by genetic predisposition, and over 100 loci have been established as associated with susceptibility. However, the biologically relevant variants underlying disease risk have not been defined for the vast majority of these loci, limiting the power of these genetic studies to define new avenues of research for the development of MS therapeutics. It is therefore crucial that candidate MS susceptibility loci are carefully investigated to identify the biological mechanism linking genetic polymorphism at a given gene to the increased chance of developing MS. MERTK has been established as an MS susceptibility gene and is part of a family of receptor tyrosine kinases known to be involved in the pathogenesis of demyelinating disease. In this study we have refined the association of MERTK with MS risk to independent signals from both common and low frequency variants. One of the associated variants was also found to be linked with increased expression of MERTK in monocytes and higher expression of MERTK was associated with either increased or decreased risk of developing MS, dependent upon HLA-DRB1*15:01 status. This discordant association potentially extended beyond MS susceptibility to alterations in disease course in established MS. This study provides clear evidence that distinct polymorphisms within MERTK are associated with MS susceptibility, one of which has the potential to alter MERTK transcription, which in turn can alter both susceptibility and disease course in MS patients.
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2016 |
Sanders KA, Benton MC, Lea RA, Maltby VE, Agland S, Griffin N, et al., 'Next-generation sequencing reveals broad down-regulation of microRNAs in secondary progressive multiple sclerosis CD4+T cells', CLINICAL EPIGENETICS, 8 (2016) [C1]
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2016 |
Lener MR, Scott RJ, Wiechowska-Kozlowska A, Serrano-Fernández P, Baszuk P, Jaworska-Bieniek K, et al., 'Serum concentrations of selenium and copper in patients diagnosed with pancreatic cancer', Cancer Research and Treatment, 48 1056-1064 (2016) [C1]
Purpose Understanding of the etiology and pathogenesis of pancreatic cancer (PaCa) is still insufficient. This study evaluated the associations between concentrations of selenium ... [more]
Purpose Understanding of the etiology and pathogenesis of pancreatic cancer (PaCa) is still insufficient. This study evaluated the associations between concentrations of selenium (Se) and copper (Cu) in the serum of PaCa patients. Materials and Methods The study included 100 PaCa patients and 100 control subjects from the same geographical region in Poland. To determine the average concentration of Se, Cu, and ratio Cu:Se in the Polish population, assay for Se and Cu was performed in 480 healthy individuals. Serum levels of Se and Cu were measured using inductively coupled plasma mass spectrometry. Results In the control group, the average Se level was 76 µg/L and Cu 1,098 µg/L. The average Se level among PaCa patients was 60 µg/L and the mean Cu level was 1,432 µg/L. The threshold point at which any decrease in Se concentration was associated with PaCa was 67.45 µg/L. The threshold point of Cu level above which there was an increase in the prevalence of PaCa was 1,214.58 µg/L. In addition, a positive relationship was observed between increasing survival time and Se plasma level. Conclusion This retrospective study suggests that low levels of Se and high levels of Cu might influence development of PaCa and that higher levels of Se are associated with longer survival in patients with PaCa. The results suggest that determining the level of Se and Cu could be incorporated into a risk stratification scheme for the selection and surveillance control examination to complement existing screening and diagnostic procedures.
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Painter JN, Kaufmann S, O'Mara TA, Hillman KM, Sivakumaran H, Darabi H, et al., 'A Common Variant at the 14q32 Endometrial Cancer Risk Locus Activates AKT1 through YY1 Binding', American Journal of Human Genetics, 98 1159-1169 (2016) [C1]
A recent meta-analysis of multiple genome-wide association and follow-up endometrial cancer case-control datasets identified a novel genetic risk locus for this disease at chromos... [more]
A recent meta-analysis of multiple genome-wide association and follow-up endometrial cancer case-control datasets identified a novel genetic risk locus for this disease at chromosome 14q32.33. To prioritize the functional SNP(s) and target gene(s) at this locus, we employed an in silico fine-mapping approach using genotyped and imputed SNP data for 6,608 endometrial cancer cases and 37,925 controls of European ancestry. Association and functional analyses provide evidence that the best candidate causal SNP is rs2494737. Multiple experimental analyses show that SNP rs2494737 maps to a silencer element located within AKT1, a member of the PI3K/AKT/MTOR intracellular signaling pathway activated in endometrial tumors. The rs2494737 risk A allele creates a YY1 transcription factor-binding site and abrogates the silencer activity in luciferase assays, an effect mimicked by transfection of YY1 siRNA. Our findings suggest YY1 is a positive regulator of AKT1, mediating the stimulatory effects of rs2494737 increasing endometrial cancer risk. Identification of an endometrial cancer risk allele within a member of the PI3K/AKT signaling pathway, more commonly activated in tumors by somatic alterations, raises the possibility that well tolerated inhibitors targeting this pathway could be candidates for evaluation as chemopreventive agents in individuals at high risk of developing endometrial cancer.
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2016 |
Sjursen W, McPhillips M, Scott RJ, Talseth-Palmer BA, 'Lynch syndrome mutation spectrum in New South Wales, Australia, including 55 novel mutations.', Molecular genetics & genomic medicine, 4 223-231 (2016) [C1]
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2016 |
Groen K, Maltby VE, Sanders KA, Scott RJ, Tajouri L, Lechner-Scott J, 'Erythrocytes in multiple sclerosis - forgotten contributors to the pathophysiology?', Multiple Sclerosis Journal Experimental, Translational and Clinical, 2 2055217316649981-2055217316649981 (2016) [C1]
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Wu JQ, Green MJ, Gardiner EJ, Tooney PA, Scott RJ, Carr VJ, Cairns MJ, 'Altered neural signaling and immune pathways in peripheral blood mononuclear cells of schizophrenia patients with cognitive impairment: A transcriptome analysis', Brain, Behavior, and Immunity, 53 194-206 (2016) [C1]
Cognitive deficits are a core feature of schizophrenia and contribute significantly to functional disability. We investigated the molecular pathways associated with schizophrenia ... [more]
Cognitive deficits are a core feature of schizophrenia and contribute significantly to functional disability. We investigated the molecular pathways associated with schizophrenia (SZ; n = 47) cases representing both 'cognitive deficit' (CD; n = 22) and 'cognitively spared' (CS; n = 25) subtypes of schizophrenia (based on latent class analysis of 9 cognitive performance indicators), compared with 49 healthy controls displaying 'normal' cognition. This was accomplished using gene-set analysis of transcriptome data derived from peripheral blood mononuclear cells (PBMCs). We detected 27 significantly altered pathways (19 pathways up-regulated and 8 down-regulated) in the combined SZ group and a further 6 pathways up-regulated in the CS group and 5 altered pathways (4 down-regulated and 1 up-regulated) in the CD group. The transcriptome profiling in SZ and cognitive subtypes were characterized by the up-regulated pathways involved in immune dysfunction (e.g., antigen presentation in SZ), energy metabolism (e.g., oxidative phosphorylation), and down-regulation of the pathways involved in neuronal signaling (e.g., WNT in SZ/CD and ERBB in SZ). When we looked for pathways that differentiated the two cognitive subtypes we found that the WNT signaling was significantly down-regulated (FDR < 0.05) in the CD group in accordance with the combined SZ cohort, whereas it was unaffected in the CS group. This suggested suppression of WNT signaling was a defining feature of cognitive decline in schizophrenia. The WNT pathway plays a role in both the development/function of the central nervous system and peripheral tissues, therefore its alteration in PBMCs may be indicative of an important genomic axis relevant to cognition in the neuropathology of schizophrenia.
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Walker MM, Keely SJ, Scott RJ, Talley NJ, 'Genetics, Mucosal Inflammation and the Environment in Post-Infectious Chronic Gut Syndromes', The American Journal of Gastroenterology Supplements, 3 46-51 (2016) [C1]
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Hess JL, Tylee DS, Barve R, de Jong S, Ophoff RA, Kumarasinghe N, et al., 'Transcriptome-wide mega-analyses reveal joint dysregulation of immunologic genes and transcription regulators in brain and blood in schizophrenia', Schizophrenia Research, 176 114-124 (2016) [C1]
The application of microarray technology in schizophrenia research was heralded as paradigm-shifting, as it allowed for high-throughput assessment of cell and tissue function. Thi... [more]
The application of microarray technology in schizophrenia research was heralded as paradigm-shifting, as it allowed for high-throughput assessment of cell and tissue function. This technology was widely adopted, initially in studies of postmortem brain tissue, and later in studies of peripheral blood. The collective body of schizophrenia microarray literature contains apparent inconsistencies between studies, with failures to replicate top hits, in part due to small sample sizes, cohort-specific effects, differences in array types, and other confounders. In an attempt to summarize existing studies of schizophrenia cases and non-related comparison subjects, we performed two mega-analyses of a combined set of microarray data from postmortem prefrontal cortices (n = 315) and from ex-vivo blood tissues (n = 578). We adjusted regression models per gene to remove non-significant covariates, providing best-estimates of transcripts dysregulated in schizophrenia. We also examined dysregulation of functionally related gene sets and gene co-expression modules, and assessed enrichment of cell types and genetic risk factors. The identities of the most significantly dysregulated genes were largely distinct for each tissue, but the findings indicated common emergent biological functions (e.g. immunity) and regulatory factors (e.g., predicted targets of transcription factors and miRNA species across tissues). Our network-based analyses converged upon similar patterns of heightened innate immune gene expression in both brain and blood in schizophrenia. We also constructed generalizable machine-learning classifiers using the blood-based microarray data. Our study provides an informative atlas for future pathophysiologic and biomarker studies of schizophrenia.
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Chen MM, O'Mara TA, Thompson DJ, Painter JN, Attia J, Black A, et al., 'GWAS meta-analysis of 16 852 women identifies new susceptibility locus for endometrial cancer', Human molecular genetics, 25 2612-2620 (2016)
Endometrial cancer is the most common gynecological malignancy in the developed world. Although there is evidence of genetic predisposition to the disease, most of the genetic ris... [more]
Endometrial cancer is the most common gynecological malignancy in the developed world. Although there is evidence of genetic predisposition to the disease, most of the genetic risk remains unexplained. We present the meta-analysis results of four genome-wide association studies (4907 cases and 11 945 controls total) in women of European ancestry. We describe one new locus reaching genome-wide significance (P < 5 × 10 -8) at 6p22.3 (rs1740828; P = 2.29 × 10 -8, OR = 1.20), providing evidence of an additional region of interest for genetic susceptibility to endometrial cancer.
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Pelttari LM, Khan S, Vuorela M, Kiiski JI, Vilske S, Nevanlinna V, et al., 'RAD51B in familial breast cancer', PLoS ONE, 11 (2016) [C1]
Common variation on 14q24.1, close to RAD51B, has been associated with breast cancer: rs999737 and rs2588809 with the risk of female breast cancer and rs1314913 with the risk of m... [more]
Common variation on 14q24.1, close to RAD51B, has been associated with breast cancer: rs999737 and rs2588809 with the risk of female breast cancer and rs1314913 with the risk of male breast cancer. The aim of this study was to investigate the role of RAD51B variants in breast cancer predisposition, particularly in the context of familial breast cancer in Finland. We sequenced the coding region of RAD51B in 168 Finnish breast cancer patients from the Helsinki region for identification of possible recurrent founder mutations. In addition, we studied the known rs999737, rs2588809, and rs1314913 SNPs and RAD51B haplotypes in 44,791 breast cancer cases and 43,583 controls from 40 studies participating in the Breast Cancer Association Consortium (BCAC) that were genotyped on a custom chip (iCOGS). We identified one putatively pathogenic missense mutation c.541C>T among the Finnish cancer patients and subsequently genotyped the mutation in additional breast cancer cases (n = 5259) and population controls (n = 3586) from Finland and Belarus. No significant association with breast cancer risk was seen in the meta-analysis of the Finnish datasets or in the large BCAC dataset. The association with previously identified risk variants rs999737, rs2588809, and rs1314913 was replicated among all breast cancer cases and also among familial cases in the BCAC dataset. The most significant association was observed for the haplotype carrying the risk-alleles of all the three SNPs both among all cases (odds ratio (OR): 1.15, 95% confidence interval (CI): 1.11-1.19, P = 8.88 × 10-16) and among familial cases (OR: 1.24, 95% CI: 1.16-1.32, P = 6.19 × 10-11), compared to the haplotype with the respective protective alleles. Our results suggest that loss-of-function mutations in RAD51B are rare, but common variation at the RAD51B region is significantly associated with familial breast cancer risk.
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Morten BC, Scott RJ, Avery-Kiejda KA, 'Comparison of three different methods for determining cell proliferation in breast cancer cell lines', Journal of Visualized Experiments, 2016 (2016) [C1]
Measuring cell proliferation can be performed by a number of different methods, each with varying levels of sensitivity, reproducibility and compatibility with high-throughput for... [more]
Measuring cell proliferation can be performed by a number of different methods, each with varying levels of sensitivity, reproducibility and compatibility with high-throughput formatting. This protocol describes the use of three different methods for measuring cell proliferation in vitro including conventional hemocytometer counting chamber, a luminescence-based assay that utilizes the change in the metabolic activity of viable cells as a measure of the relative number of cells, and a multi-mode cell imager that measures cell number using a counting algorithm. Each method presents its own advantages and disadvantages for the measurement of cell proliferation, including time, cost and high-throughput compatibility. This protocol demonstrates that each method could accurately measure cell proliferation over time, and was sensitive to detect growth at differing cellular densities. Additionally, measurement of cell proliferation using a cell imager was able to provide further information such as morphology, confluence and allowed for a continual monitoring of cell proliferation over time. In conclusion, each method is capable of measuring cell proliferation, but the chosen method is user-dependent.
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Hauberg ME, Roussos P, Grove J, Børglum AD, Mattheisen M, 'Analyzing the Role of MicroRNAs in Schizophrenia in the Context of Common Genetic Risk Variants', JAMA Psychiatry, 73 369-369 (2016) [C1]
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Morten BC, Scott RJ, Avery-Kiejda KA, 'Comparison of the QuantiGene 2.0 assay and real-time RT-PCR in the detection of p53 isoform mRNA expression in formalin-fixed paraffin-embedded tissues- A preliminary study', PLoS ONE, 11 (2016) [C1]
p53 is expressed as multiple smaller isoforms whose functions in cancer are not well understood. The p53 isoforms demonstrate abnormal expression in different cancers, suggesting ... [more]
p53 is expressed as multiple smaller isoforms whose functions in cancer are not well understood. The p53 isoforms demonstrate abnormal expression in different cancers, suggesting they are important in modulating the function of full-length p53 (FLp53). The quantification of relative mRNA expression has routinely been performed using real-time PCR (qPCR). However, there are serious limitations when detecting p53 isoforms using this method, particularly for formalin-fixed paraffin-embedded (FFPE) tissues. The use of FFPE tumours would be advantageous to correlate expression of p53 isoforms with important clinical features of cancer. One alternative method of RNA detection is the hybridization-based QuantiGene 2.0 Assay, which has been shown to be advantageous for the detection of RNA from FFPE tissues. In this pilot study, we compared the QuantiGene 2.0 Assay to qPCR for the detection of FLp53 and its isoform ¿40p53 in matched fresh frozen (FF) and FFPE breast tumours. FLp53 mRNA expression was detected using qPCR in FF and FFPE tissues, but ¿40p53 mRNA was only detectable in FF tissues. Similar results were obtained for the QuantiGene 2.0 Assay. FLp53 relative mRNA expression was shown to be strongly correlated between the two methods (R2 = 0.9927, p = 0.0031) in FF tissues, however ¿40p53 was not (R2 = 0.4429, p = 0.3345). When comparing the different methods for the detection of FLp53 mRNA from FFPE and FF samples, no correlation (R2 = 0.0002, p = 0.9863) was shown using the QuantiGene 2.0 Assay, and in contrast, the level of expression was highly correlated between the two tissues using qPCR (R2 = 0.8753, p = 0.0644). These results suggest that both the QuantiGene 2.0 Assay and qPCR methods are inadequate for the quantification of ¿40p53 mRNA in FFPE tissues. Therefore, alternative methods of RNA detection and quantification are required to study the relative expression of ¿40p53 in FFPE samples.
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Johnson NA, Kypri K, Latter J, Attia J, McEvoy M, Dunlop A, Scott R, 'Genetic feedback to reduce alcohol consumption in hospital outpatients with risky drinking: Feasibility and acceptability', Public Health Research and Practice, 26 (2016) [C1]
Objective: There have been no trials in healthcare settings of genetic susceptibility feedback in relation to alcohol consumption. The purpose of this study was to determine the f... [more]
Objective: There have been no trials in healthcare settings of genetic susceptibility feedback in relation to alcohol consumption. The purpose of this study was to determine the feasibility and acceptability of conducting a full-scale randomised trial estimating the effect of personalised genetic susceptibility feedback on alcohol consumption in hospital outpatients with risky drinking. Methods: Outpatients =18 years of age who reported drinking more than 14 standard drinks in the past week or in a typical week were asked to provide a saliva sample for genetic testing. Genetic susceptibility feedback was posted to participants 6 months after recruitment. The co-primary outcomes were the proportion of participants who (i) provided a saliva sample that could be genotyped, and (ii) spoke with a genetic counsellor. Secondary outcomes included changes in patients' weekly alcohol consumption; scores on scales measuring readiness to change, importance of changing and confidence in ability to change drinking habits; knowledge about which cancers are alcohol-attributable; and acceptability of the saliva collection procedure and the genetic-feedback intervention. McNemar's test and paired t-tests were used to test for differences between baseline and follow-up in proportions and means, respectively. Results: Of 100 participants who provided a saliva sample, 93 had adequate DNA for at least one genotyping assay. Three participants spoke to a genetic counsellor. Patients' readiness to change their drinking, their views on the importance of changing and their stated confidence in their ability to change increased between baseline and follow-up. There was no increase in patients' knowledge about alcohol-attributable cancers nor any reduction in how much alcohol they drank 4 months after receiving the feedback. Most participants (80%) were somewhat comfortable or very comfortable with the process used to collect saliva, 84% understood the genetic feedback, 54% found it useful, 10% had sought support to reduce their drinking after receiving the feedback, and 37% reported that the feedback would affect how much they drink in the future. Conclusion: Results of this study suggest it would be feasible to conduct a methodologically robust trial estimating the effect of genetic susceptibility feedback on alcohol consumption in hospital outpatients with risky drinking.
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2016 |
Wong SQ, Scott R, Fox SB, 'KRAS mutation testing in colorectal cancer: the model for molecular pathology testing in the future', COLORECTAL CANCER, 5 73-80 (2016) [C1]
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2016 |
Okbay A, Beauchamp JP, Fontana MA, Lee JJ, Pers TH, Rietveld CA, et al., 'Genome-wide association study identifies 74 loci associated with educational attainment.', Nature, 533 539-542 (2016) [C1]
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2016 |
Southey MC, Goldgar DE, Winqvist R, Pylkäs K, Couch F, Tischkowitz M, et al., 'PALB2, CHEK2 and ATM rare variants and cancer risk: Data from COGS', Journal of Medical Genetics, 53 800-811 (2016) [C1]
Background The rarity of mutations in PALB2, CHEK2 and ATM make it difficult to estimate precisely associated cancer risks. Population-based family studies have provided evidence ... [more]
Background The rarity of mutations in PALB2, CHEK2 and ATM make it difficult to estimate precisely associated cancer risks. Population-based family studies have provided evidence that at least some of these mutations are associated with breast cancer risk as high as those associated with rare BRCA2 mutations. We aimed to estimate the relative risks associated with specific rare variants in PALB2, CHEK2 and ATM via a multicentre case-control study. Methods We genotyped 10 rare mutations using the custom iCOGS array: PALB2 c.1592delT, c.2816T > G and c.3113G > A, CHEK2 c.349A > G, c.538C > T, c.715G > A, c.1036C > T, c.1312G > T, and c.1343T > G and ATM c.7271T > G. We assessed associations with breast cancer risk (42 671 cases and 42 164 controls), as well as prostate (22 301 cases and 22 320 controls) and ovarian (14 542 cases and 23 491 controls) cancer risk, for each variant. Results For European women, strong evidence of association with breast cancer risk was observed for PALB2 c.1592delT OR 3.44 (95% CI 1.39 to 8.52, p=7.1×10-5), PALB2 c.3113G > A OR 4.21 (95% CI 1.84 to 9.60, p=6.9×10-8) and ATM c.7271T > G OR 11.0 (95% CI 1.42 to 85.7, p=0.0012). We also found evidence of association with breast cancer risk for three variants in CHEK2, c.349A > G OR 2.26 (95% CI 1.29 to 3.95), c.1036C > T OR 5.06 (95% CI 1.09 to 23.5) and c.538C > T OR 1.33 (95% CI 1.05 to 1.67) (p=0.017). Evidence for prostate cancer risk was observed for CHEK2 c.1343T > G OR 3.03 (95% CI 1.53 to 6.03, p=0.0006) for African men and CHEK2 c.1312G > T OR 2.21 (95% CI 1.06 to 4.63, p=0.030) for European men. No evidence of association with ovarian cancer was found for any of these variants. Conclusions This report adds to accumulating evidence that at least some variants in these genes are associated with an increased risk of breast cancer that is clinically important.
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2016 |
Marioni RE, Ritchie SJ, Joshi PK, Hagenaars SP, Okbay A, Fischer K, et al., 'Genetic variants linked to education predict longevity', Proceedings of the National Academy of Sciences of the United States of America, 113 13366-13371 (2016) [C1]
Educational attainment is associated with many health outcomes, including longevity. It is also known to be substantially heritable. Here, we used data from three large genetic ep... [more]
Educational attainment is associated with many health outcomes, including longevity. It is also known to be substantially heritable. Here, we used data from three large genetic epidemiology cohort studies (Generation Scotland, n = ~17,000; UK Biobank, n = ~115,000; and the Estonian Biobank, n = ~6,000) to test whether education-linked genetic variants can predict lifespan length. We did so by using cohort members' polygenic profile score for education to predict their parents' longevity. Across the three cohorts, meta-analysis showed that a 1 SD higher polygenic education score was associated with ~2.7% lower mortality risk for both mothers (total ndeaths= 79,702) and ~2.4% lower risk for fathers (total ndeaths= 97,630). On average, the parents of offspring in the upper third of the polygenic score distribution lived 0.55 y longer compared with those of offspring in the lower third. Overall, these results indicate that the genetic contributions to educational attainment are useful in the prediction of human longevity.
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2016 |
Tan AG, Kifley A, Mitchell P, Rochtchina E, Flood VM, Cumming RG, et al., 'Associations between methylenetetrahydrofolate reductase polymorphisms, serum homocysteine levels, and incident cortical cataract', JAMA Ophthalmology, 134 522-528 (2016) [C1]
IMPORTANCE Methylenetetrahydrofolate reductase (MTHFR) polymorphisms have been shown to influence homocysteine levels; homocysteine has been implicated as a cataractogenic stresso... [more]
IMPORTANCE Methylenetetrahydrofolate reductase (MTHFR) polymorphisms have been shown to influence homocysteine levels; homocysteine has been implicated as a cataractogenic stressor. OBJECTIVE To investigate the associations of MTHFR polymorphisms and serum homocysteine levels with incident cortical cataract in an older population. DESIGN, SETTING, AND PARTICIPANTS From 1992 to 1994, a population-based cohort study, the Blue Mountains Eye Study, was conducted with 3654 residents (82.4%of eligible participants) of the Blue Mountains region aged 49 years and older. At the second (1997-1999, 5-year follow-up) and third (2002-2004, 10-year follow-up) surveys, 2334 (75.8% of survivors) and 1952 (76.7%of survivors) were examined, respectively. For this report, the second survey serves as baseline when homocysteine levels were assessed, and 5-year incidence of cataract refers to incidence estimated from the second to the third survey. After excluding participants with no follow-up data or DNA or who had previous cortical cataract or cataract surgery, 757 participants were included in gene and environment analyses. This current project on associations with cataract was designed initially March 19, 2013, and completed April 14, 2014. Cataract was assessed using the Wisconsin Cataract Grading system. Two MTHFR polymorphisms, C677T (rs1801133) and A1298C (rs1801131), were included. Serum homocysteine levels were assessed following standard methods. MAIN OUTCOMES AND MEASURES Logistic regression modelswere used to estimate odds ratios (ORs) and 95%confidence intervals for incident cortical cataract, after adjusting for age, sex, smoking status, hypertension, diabetes, education, andmyopia. Path analysis was performed to explore a possible pathway of MTHFR polymorphisms via homocysteine levels to cortical cataract. RESULTS The mean (SD) age of the 1726 participants in the Blue Mountains Eye Study 2 cohort with normal homocysteine levels was 68.3 (8.1) years and 73.2 (8.5) years for those with elevated homocysteine levels. Both the C677T polymorphism (CT/TT vs CC: OR = 1.50; 95%CI = 1.01-2.23) and elevated homocysteine levels (>15 ìmol/L: OR = 2.24; 95% CI = 1.38-3.63) were independently associated with increased risk of cortical cataract. Path analysis showed that the genetic effect on cortical cataract was partially mediated via homocysteine levels. Combined CT/TT genotypes and elevated homocysteine levels were associated with a 3-fold risk of cortical cataract (OR = 3.74; 95%CI = 1.79-7.80). The synergy index of both exposures was 1.34 (95%CI = 0.44-4.01). CONCLUSIONS AND RELEVANCE MTHFR polymorphism and elevated homocysteine levels contributed separately and jointly to increased risk of cortical cataract. If these findings are confirmed, homocysteine levels may be a therapeutic target to reduce risk of cortical cataract in persons carrying genetic risk.
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2016 |
Easton DF, Lesueur F, Decker B, Michailidou K, Li J, Allen J, et al., 'No evidence that protein truncating variants in
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2016 |
Franke B, Stein JL, Ripke S, Anttila V, Hibar DP, van Hulzen KJE, et al., 'Genetic influences on schizophrenia and subcortical brain volumes: large-scale proof of concept', Nature Neuroscience, 19 420-431 (2016) [C1]
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2016 |
Wong-Brown M, McPhillips M, Gleeson M, Spigelman AD, Meldrum CJ, Dooley S, Scott RJ, 'When is a mutation not a mutation: the case of the c.594-2A\C splice variant in a woman harbouring another BRCA1 mutation in trans.', Hered Cancer Clin Pract, 14 6 (2016) [C1]
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Nova |
2016 |
Bolton KA, Avery-Kiejda KA, Holliday EG, Attia J, Bowden NA, Scott RJ, 'A polymorphic repeat in the IGF1 promoter influences the risk of endometrial cancer', ENDOCRINE CONNECTIONS, 5 115-122 (2016) [C1]
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Nova |
2016 |
Li N, Thompson ER, Rowley SM, McInerny S, Devereux L, Goode D, et al., 'Reevaluation of RINT1 as a breast cancer predisposition gene', Breast Cancer Research and Treatment, 159 385-392 (2016) [C1]
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2016 |
Thompson DJ, O'Mara TA, Glubb DM, Painter JN, Cheng T, Folkerd E, et al., 'CYP19A1 fine-mapping and Mendelian randomization: Estradiol is causal for endometrial cancer', Endocrine-Related Cancer, 23 77-91 (2016) [C1]
Candidate gene studies have reported CYP19A1 variants to be associated with endometrial cancerandwith estradiol (E2) concentrations.We analyzed2937singlenucleotidepolymorphisms (S... [more]
Candidate gene studies have reported CYP19A1 variants to be associated with endometrial cancerandwith estradiol (E2) concentrations.We analyzed2937singlenucleotidepolymorphisms (SNPs) in 6608 endometrial cancer cases and 37 925 controls and report the first genome widesignificant association between endometrial cancer and a CYP19A1 SNP (rs727479 in intron 2, P=4.8×10-11). SNP rs727479 was also among those most strongly associated with circulating E2 concentrations in 2767 post-menopausal controls (P=7.4×10-8). The observed endometrial cancer odds ratio per rs727479 A-allele (1.15, CI=1.11-1.21) is compatible with that predicted by theobservedeffectonE2 concentrations (1.09, CI=1.03-1.21), consistentwith the hypothesis that endometrial cancer risk is driven by E2. From 28 candidate-causal SNPs, 12 co-located with three putative gene-regulatory elements and their risk alleles associated with higher CYP19A1 expression in bioinformatical analyses. For both phenotypes, the associationswith rs727479 were stronger amongwomen with a higher BMI (PinteractionZ0.034 and 0.066 respectively), suggesting a biologically plausible gene-environment interaction.
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2016 |
Sekar A, Bialas AR, de Rivera H, Davis A, Hammond TR, Kamitaki N, et al., 'Schizophrenia risk from complex variation of complement component 4', Nature, 530 177-183 (2016) [C1]
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Nova |
2016 |
Morten BC, Wong-Brown MW, Scott RJ, Avery-Kiejda KA, 'The presence of the intron 3 16 bp duplication polymorphism of p53 (rs17878362) in breast cancer is associated with a low 40p53:p53 ratio and better outcome', Carcinogenesis, 37 81-86 (2016) [C1]
Breast cancer is the most common female cancer, but it has relatively low rates of p53 mutations, suggesting other mechanisms are responsible for p53 inactivation. We have shown t... [more]
Breast cancer is the most common female cancer, but it has relatively low rates of p53 mutations, suggesting other mechanisms are responsible for p53 inactivation. We have shown that the p53 isoform, ¿40p53, is highly expressed in breast cancer, where it may contribute to p53 inactivation. ¿40p53 can be produced by alternative splicing of p53 in intron 2 and this is regulated by the formation of G-quadruplex structures in p53 intron 3, from which the nucleotides forming these structures overlap with a common polymorphism, rs17878362. rs17878362 alters p53 splicing to decrease fully spliced p53 messenger RNA (mRNA) in vitro following ionizing radiation and this in turn alters ¿40p53:p53. Hence, the presence of rs17878362 may be important in regulating ¿40p53:p53 in breast cancer. This study aimed to determine if rs17878362 was associated with altered ¿40p53 and p53 expression and outcome in breast cancer. We sequenced p53 in breast tumours from 139 patients and compared this with ¿40p53 and p53 mRNA expression. We found that the ratio of ¿40p53:p53 was significantly lower in tumours homozygous for the polymorphic A2 allele compared with those who were wild-type (A1/A1). Furthermore, there was a lower proportion of breast cancers carrying the A2 allele from patients who subsequently developed metastasis compared with those that did not. Finally, we show that patients whose tumours carried the polymorphic A2 allele had significantly better disease-free survival. These results show that rs17878362 is associated with a low ¿40p53:p53 ratio in breast cancer and that this is associated with better outcome.
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2016 |
Grimson S, Cox AJ, Pringle KG, Burns C, Lumbers ER, Blackwell CC, Scott RJ, 'The prevalence of unique SNPs in the renin-angiotensin system highlights the need for pharmacogenetics in Indigenous Australians', Clinical and Experimental Pharmacology and Physiology, 43 157-160 (2016) [C1]
Genetic differences between ethnic populations affect susceptibility to disease and efficacy of drugs. This study examined and compared the prevalence of single nucleotide polymor... [more]
Genetic differences between ethnic populations affect susceptibility to disease and efficacy of drugs. This study examined and compared the prevalence of single nucleotide polymorphisms (SNPs) in genes of the renin-angiotensin system (RAS) in a desert community of Indigenous Australians and in non-Indigenous Australians. The polymorphisms were angiotensinogen, AGT G-217A (rs5049); AGT G+174A (rs4762); Angiotensin II type 1 receptor, AGTR1 A+1166C (rs5186); angiotensin converting enzyme, ACE A-240T (rs4291), ACE T-93C (rs4292); renin, REN T+1142C (rs5706). They were measured using allelic discrimination assays. The prevalence of REN T+1142C SNP was similar in the two populations; 99% were homozygous for the T allele. All other SNPs were differently distributed between the two populations (P < 0.0001). In non-Indigenous Australians, the A allele at position 204 of ACE rs4291 was prevalent (61.8%) whereas in the Indigenous Australians the A allele was less prevalent (28%). For rs4292, the C allele had a prevalence of 37.9% in non-Indigenous Australians but in Indigenous Australians the prevalence was only 1%. No Indigenous individuals were homozygous for the C allele of AGTR1 (rs5186). Thus the prevalence of RAS SNPs in this Indigenous Australian desert community was different from non-Indigenous Australians as was the prevalence of cytokine SNPs (as shown in a previous study). These differences may affect susceptibility to chronic renal and cardiovascular disease and may alter the efficacy of drugs used to inhibit the RAS. These studies highlight the need to study the pharmacogenetics of drug absorption, distribution, metabolism and excretion in Indigenous Australians for safe prescribing guidelines.
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2016 |
Masson AL, Talseth-Palmer BA, Evans TJ, McElduff P, Spigelman AD, Hannan GN, Scott RJ, 'Copy number variants associated with 18p11.32, DCC and the promoter 1B region of APC in colorectal polyposis patients', Meta Gene, 7 95-104 (2016) [C1]
Familial Adenomatous Polyposis (FAP) is the second most common inherited predisposition to colorectal cancer (CRC) associated with the development of hundreds to thousands of aden... [more]
Familial Adenomatous Polyposis (FAP) is the second most common inherited predisposition to colorectal cancer (CRC) associated with the development of hundreds to thousands of adenomas in the colon and rectum. Mutations in APC are found in ~. 80% polyposis patients with FAP. In the remaining 20% no genetic diagnosis can be provided suggesting other genes or mechanisms that render APC inactive may be responsible. Copy number variants (CNVs) remain to be investigated in FAP and may account for disease in a proportion of polyposis patients. A cohort of 56 polyposis patients and 40 controls were screened for CNVs using the 2.7M microarray (Affymetrix) with data analysed using ChAS (Affymetrix). A total of 142 CNVs were identified unique to the polyposis cohort suggesting their involvement in CRC risk. We specifically identified CNVs in four unrelated polyposis patients among CRC susceptibility genes APC, DCC, MLH1 and CTNNB1 which are likely to have contributed to disease development in these patients. A recurrent deletion was observed at position 18p11.32 in 9% of the patients screened that was of particular interest. Further investigation is necessary to fully understand the role of these variants in CRC risk given the high prevalence among the patients screened.
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2016 |
Ibrahim-Verbaas CA, Bressler J, Debette S, Schuur M, Smith AV, Bis JC, et al., 'GWAS for executive function and processing speed suggests involvement of the CADM2 gene', Molecular Psychiatry, 21 189-197 (2016) [C1]
To identify common variants contributing to normal variation in two specific domains of cognitive functioning, we conducted a genome-wide association study (GWAS) of executive fun... [more]
To identify common variants contributing to normal variation in two specific domains of cognitive functioning, we conducted a genome-wide association study (GWAS) of executive functioning and information processing speed in non-demented older adults from the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) consortium. Neuropsychological testing was available for 5429-32 070 subjects of European ancestry aged 45 years or older, free of dementia and clinical stroke at the time of cognitive testing from 20 cohorts in the discovery phase. We analyzed performance on the Trail Making Test parts A and B, the Letter Digit Substitution Test (LDST), the Digit Symbol Substitution Task (DSST), semantic and phonemic fluency tests, and the Stroop Color and Word Test. Replication was sought in 1311-21860 subjects from 20 independent cohorts. A significant association was observed in the discovery cohorts for the single-nucleotide polymorphism (SNP) rs17518584 (discovery P-value=3.12 × 10 -8) and in the joint discovery and replication meta-analysis (P-value=3.28 × 10 -9 after adjustment for age, gender and education) in an intron of the gene cell adhesion molecule 2 (CADM2) for performance on the LDST/DSST. Rs17518584 is located about 170 kb upstream of the transcription start site of the major transcript for the CADM2 gene, but is within an intron of a variant transcript that includes an alternative first exon. The variant is associated with expression of CADM2 in the cingulate cortex (P-value=4 × 10 -4). The protein encoded by CADM2 is involved in glutamate signaling (P-value=7.22 × 10 -15), gamma-aminobutyric acid (GABA) transport (P-value=1.36 × 10 -11) and neuron cell-cell adhesion (P-value=1.48 × 10 -13). Our findings suggest that genetic variation in the CADM2 gene is associated with individual differences in information processing speed.
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2016 |
Bolton KA, Holliday EG, Attia J, Bowden NA, Avery-Kiejda KA, Scott RJ, 'A novel polymorphic repeat in the upstream regulatory region of the estrogen-induced gene EIG121 is not associated with the risk of developing breast or endometrial cancer', BMC Research Notes, 9 (2016) [C1]
Background: The estrogen-induced gene 121 (EIG121) has been associated with breast and endometrial cancers, but its mechanism of action remains unknown. In a genome-wide search fo... [more]
Background: The estrogen-induced gene 121 (EIG121) has been associated with breast and endometrial cancers, but its mechanism of action remains unknown. In a genome-wide search for tandem repeats, we found that EIG121 contains a short tandem repeat (STR) in its upstream regulatory region which has the potential to alter gene expression. The presence of this STR has not previously been analysed in relation to breast or endometrial cancer risk. Results: In this study, the lengths of this STR were determined by PCR, fragment analysis and sequencing using DNA from 223 breast cancer patients, 204 endometrial cancer patients and 220 healthy controls to determine if they were associated with the risk of developing breast or endometrial cancer. We found this repeat to be highly variable with the number of copies of the AG motif ranging from 27 to 72 and having a bimodal distribution. No statistically significant association was identified between the length of this STR and the risk of developing breast or endometrial cancer or age at diagnosis. Conclusions: The STR in the upstream regulatory region of EIG121 is highly polymorphic, but is not associated with the risk of developing breast or endometrial cancer in the cohorts analysed here. While this polymorphic STR in the regulatory region of EIG121 appears to have no impact on the risk of developing breast or endometrial cancer, its association with disease recurrence or overall survival remains to be determined.
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2016 |
Bigdeli TB, Ripke S, Bacanu S, Lee SH, Wray NR, Gejman PV, et al., 'Genome-wide association study reveals greater polygenic loading for schizophrenia in cases with a family history of illness', American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 171 276-289 (2016) [C1]
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2016 |
Lubinski J, Scott RJ, Sijmons R, Theissen SM, 'Thank you to all our manuscript reviewers in 2015.', Hered Cancer Clin Pract, 14 7 (2016)
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2016 |
Pringle KG, Delforce SJ, Wang Y, Ashton KA, Proietto A, Otton G, et al., 'Renin-angiotensin system gene polymorphisms and endometrial cancer', ENDOCRINE CONNECTIONS, 5 128-135 (2016) [C1]
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Nova |
2016 |
Guo ST, Chi MN, Yang RH, Guo XY, Zan LK, Wang CY, et al., 'INPP4B is an oncogenic regulator in human colon cancer', Oncogene, 35 3049-3061 (2016) [C1]
Inositol polyphosphate 4-phosphatase type II (INPP4B) negatively regulates phosphatidylinositol 3-kinase signaling and is a tumor suppressor in some types of cancers. However, we ... [more]
Inositol polyphosphate 4-phosphatase type II (INPP4B) negatively regulates phosphatidylinositol 3-kinase signaling and is a tumor suppressor in some types of cancers. However, we have found that it is frequently upregulated in human colon cancer cells. Here we show that silencing of INPP4B blocks activation of Akt and serum-and glucocorticoid-regulated kinase 3 (SGK3), inhibits colon cancer cell proliferation and retards colon cancer xenograft growth. Conversely, overexpression of INPP4B increases proliferation and triggers anchorage-independent growth of normal colon epithelial cells. Moreover, we demonstrate that the effect of INPP4B on Akt and SGK3 is associated with inactivation of phosphate and tensin homolog through its protein phosphatase activity and that the increase in INPP4B is due to Ets-1-mediated transcriptional upregulation in colon cancer cells. Collectively, these results suggest that INPP4B may function as an oncogenic driver in colon cancer, with potential implications for targeting INPP4B as a novel approach to treat this disease.
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2016 |
Pattaro C, Teumer A, Gorski M, Chu AY, Li M, Mijatovic V, et al., 'Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function', NATURE COMMUNICATIONS, 7 (2016) [C1]
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Nova |
2016 |
Couch FJ, Kuchenbaecker KB, Michailidou K, Mendoza-Fandino GA, Nord S, Lilyquist J, et al., 'Identification of four novel susceptibility loci for oestrogen receptor negative breast cancer', NATURE COMMUNICATIONS, 7 (2016) [C1]
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2016 |
Minelli C, Dean CH, Hind M, Alves AC, Amaral AFS, Siroux V, et al., 'Association of Forced Vital Capacity with the Developmental Gene NCOR2', PLOS ONE, 11 e0147388-e0147388 [C1]
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2016 |
Srinivasan S, Bettella F, Mattingsdal M, Wang Y, Witoelar A, Schork AJ, et al., 'Genetic Markers of Human Evolution Are Enriched in Schizophrenia', Biological Psychiatry, 80 284-292 (2016) [C1]
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2016 |
Mehta D, Tropf FC, Gratten J, Bakshi A, Zhu Z, Bacanu S-A, et al., 'Evidence for Genetic Overlap Between Schizophrenia and Age at First Birth in Women.', JAMA psychiatry, 73 497-505 (2016) [C1]
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2016 |
Wang Y, Thompson WK, Schork AJ, Holland D, Chen C-H, Bettella F, et al., 'Leveraging Genomic Annotations and Pleiotropic Enrichment for Improved Replication Rates in Schizophrenia GWAS', PLOS Genetics, 12 e1005803-e1005803 [C1]
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2016 |
Mathe A, Wong-Brown M, Locke WJ, Stirzaker C, Braye SG, Forbes JF, et al., 'DNA methylation profile of triple negative breast cancer-specific genes comparing lymph node positive patients to lymph node negative patients', SCIENTIFIC REPORTS, 6 (2016) [C1]
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2016 |
Mather KA, Thalamuthu A, Oldmeadow C, Song F, Armstrong NJ, Poljak A, et al., 'Genome-wide significant results identified for plasma apolipoprotein H levels in middle-aged and older adults', Scientific Reports, 6 (2016) [C1]
Apolipoprotein H (ApoH) is a multi-functional plasma glycoprotein that has been associated with negative health outcomes. ApoH levels have high heritability. We undertook a genome... [more]
Apolipoprotein H (ApoH) is a multi-functional plasma glycoprotein that has been associated with negative health outcomes. ApoH levels have high heritability. We undertook a genome-wide association study of ApoH levels using the largest sample to date and replicated the results in an independent cohort (total N = 1,255). In the discovery phase, a meta-analysis of two cohorts, the Sydney Memory and Ageing Study (Sydney MAS) and the Older Australian Twins Study (OATS) (n = 942) revealed genome-wide significant results in or near the APOH gene on chromosome 17 (top SNP, rs7211380, p = 1 × 10-11). The results were replicated in an independent cohort, the Hunter Community Study (p < 0.002) (n = 313). Conditional and joint analysis (COJO) confirmed the association of the chromosomal 17 region with ApoH levels. The set of independent SNPs identified by COJO explained 23% of the variance. The relationships between the top SNPs and cardiovascular/lipid/cognition measures and diabetes were assessed in Sydney MAS, with suggestive results observed for diabetes and cognitive performance. However, replication of these results in the smaller OATS cohort was not found. This work provides impetus for future research to better understand the contribution of genetics to ApoH levels and its possible impacts on health.
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2015 |
Dun MD, Chalkley RJ, Faulkner S, Keene S, Avery-Kiejda KA, Scott RJ, et al., 'Proteotranscriptomic profiling of 231-BR breast cancer cells: Identification of potential biomarkers and therapeutic targets for brain metastasis', Molecular and Cellular Proteomics, 14 2316-2330 (2015) [C1]
Brain metastases are a devastating consequence of cancer and currently there are no specific biomarkers or therapeutic targets for risk prediction, diagnosis, and treatment. Here ... [more]
Brain metastases are a devastating consequence of cancer and currently there are no specific biomarkers or therapeutic targets for risk prediction, diagnosis, and treatment. Here the proteome of the brain metastatic breast cancer cell line 231-BR has been compared with that of the parental cell line MDA-MB-231, which is also metastatic but has no organ selectivity. Using SILAC and nanoLC-MS/MS, 1957 proteins were identified in reciprocal labeling experiments and 1584 were quantified in the two cell lines. A total of 152 proteins were confidently determined to be up- or down-regulated by more than twofold in 231-BR. Of note, 112/152 proteins were decreased as compared with only 40/152 that were increased, suggesting that down-regulation of specific proteins is an important part of the mechanism underlying the ability of breast cancer cells to metastasize to the brain. When matched against transcriptomic data, 43% of individual protein changes were associated with corresponding changes in mRNA, indicating that the transcript level is a limited predictor of protein level. In addition, differential miRNA analyses showed that most miRNA changes in 231-BR were up- (36/45) as compared with down-regulations (9/45). Pathway analysis revealed that proteome changes were mostly related to cell signaling and cell cycle, metabolism and extracellular matrix remodeling. The major protein changes in 231-BR were confirmed by parallel reaction monitoring mass spectrometry and consisted in increases (by more than fivefold) in the matrix metalloproteinase-1, ephrin-B1, stomatin, myc target-1, and decreases (by more than 10-fold) in transglutaminase-2, the S100 calcium-binding protein A4, and L-plastin. The clinicopathological significance of these major proteomic changes to predict the occurrence of brain metastases, and their potential value as therapeutic targets, warrants further investigation.
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2015 |
Kurlapska A, Serrano-Fernández P, Baszuk P, Gupta S, Starzynska T, Malecka-Panas E, et al., 'Cumulative effects of genetic markers and the detection of advanced colorectal neoplasias by population screening', Clinical Genetics, 88 234-240 (2015) [C1]
Genetic markers associated with colorectal cancer may be used in population screening for the early identification of patients at elevated risk of disease. We genotyped 3059 indiv... [more]
Genetic markers associated with colorectal cancer may be used in population screening for the early identification of patients at elevated risk of disease. We genotyped 3059 individuals with no cancer family history for eight markers previously associated with colorectal cancer. After colonoscopy, the genetic profile of cases with advanced colorectal neoplasia (213) was compared with the rest (2846). rs2066847 and rs6983267 were significantly associated with the risk of advanced colorectal neoplasia but with limited effect on their own [odds ratio (OR) 1.59; 95% confidence interval (CI) 1.02-2.41; p=0.033 and OR 1.45; 95% CI 1.02-2.12; p=0.044, respectively]. Cumulative effects, in contrast, were associated with high risk: the combination of rs2066847, rs6983267, rs4779584, rs3802842 and rs4939827 minimized the number of markers considered, while maximizing the relative size of the carrier group and the risk associated to it, for example, for at least two cumulated risk markers, OR is 2.57 (95% CI 1.50-4.71; corrected p-value 0.0079) and for three or more, OR is 3.57 (95% CI 1.91-6.96; corrected p-value 0.00074). The identification of cumulative models of - otherwise - low-risk markers could be valuable in defining risk groups, within an otherwise low-risk population (no cancer family history).
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2015 |
Stirzaker C, Zotenko E, Song JZ, Qu W, Nair SS, Locke WJ, et al., 'Methylome sequencing in triple-negative breast cancer reveals distinct methylation clusters with prognostic value', Nature Communications, 6 1-11 (2015) [C1]
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2015 |
Moscovis SM, Gordon AE, Al Madani OM, Gleeson M, Scott RJ, Hall ST, et al., 'Genetic and environmental factors affecting TNF-a responses in relation to sudden infant death syndrome', Frontiers in Immunology, 6 (2015) [C1]
Dysregulation of the inflammatory responses has been suggested to contribute to the events leading to sudden infant deaths. Our objectives were (1) to analyze a single nucleotide ... [more]
Dysregulation of the inflammatory responses has been suggested to contribute to the events leading to sudden infant deaths. Our objectives were (1) to analyze a single nucleotide polymorphism (SNP) associated with high levels of tumor necrosis factor-a (TNF-a) responses, TNF G-308A, in sudden infant death syndrome (SIDS) infants, SIDS and control parents, and ethnic groups with different incidences of SIDS; (2) the effects of two risk factors for SIDS, cigarette smoke and virus infection, on TNF-a responses; and (3) to assess effects of genotype, cigarette smoke, and gender on TNF-a responses to bacterial toxins identified in SIDS infants. TNF G-308A genotypes were determined by real-time polymerase chain reaction for SIDS infants from Australia, Germany, and Hungary; parents of SIDS infants and their controls; and populations with high (Aboriginal Australian), medium (Caucasian), and low (Bangladeshi) SIDS incidences. Leukocytes from Caucasian donors were stimulated in vitro with endotoxin or toxic shock syndrome toxin-1 (TSST-1). TNF-a responses were measured by L929 bioassay (IU/ml) and assessed in relation to genotype, smoking status, and gender. There was a significantly higher proportion of the minor allele AA genotype among Australian SIDS infants (6/24, 24%) compared to 3/62 (4.8%) controls (p = 0.03). There were no significant differences in TNF-a responses by TNF G-308A genotypes when assessed in relation to smoking status or gender. Given the rarity of the TNF G-308A A allele in Caucasian populations, the finding that 24% of the Australian SIDS infants tested had this genotype requires further investigation and cautious interpretation. Although non-smokers with the AA genotype had higher TNFa responses to both TSST-1 and endotoxin, there were too few subjects with this rare allele to obtain statistically valid results. No effects of genotype, smoking, or gender were observed for TNF-a responses to these toxins.
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2015 |
Cheng THT, Thompson D, Painter J, O'Mara T, Gorman M, Martin L, et al., 'Meta-analysis of genome-wide association studies identifies common susceptibility polymorphisms for colorectal and endometrial cancer near SH2B3 and TSHZ1.', Sci Rep, 5 17369 (2015) [C1]
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2015 |
Carvajal-Carmona LG, O Mara TA, Painter JN, Lose FA, Dennis J, Michailidou K, et al., 'Candidate locus analysis of the TERT CLPTM1L cancer risk region on chromosome 5p15 identifies multiple independent variants associated with endometrial cancer risk', Human Genetics, 134 231-245 (2015) [C1]
Several studies have reported associations between multiple cancer types and single-nucleotide polymorphisms (SNPs) on chromosome 5p15, which harbours TERT and CLPTM1L, but no suc... [more]
Several studies have reported associations between multiple cancer types and single-nucleotide polymorphisms (SNPs) on chromosome 5p15, which harbours TERT and CLPTM1L, but no such association has been reported with endometrial cancer. To evaluate the role of genetic variants at the TERT¿CLPTM1L region in endometrial cancer risk, we carried out comprehensive fine-mapping analyses of genotyped and imputed SNPs using a custom Illumina iSelect array which includes dense SNP coverage of this region. We examined 396 SNPs (113 genotyped, 283 imputed) in 4,401 endometrial cancer cases and 28,758 controls. Single-SNP and forward/backward logistic regression models suggested evidence for three variants independently associated with endometrial cancer risk (P¿=¿4.9¿×¿10-6 to P¿=¿7.7¿×¿10-5). Only one falls into a haplotype previously associated with other cancer types (rs7705526, in TERT intron 1), and this SNP has been shown to alter TERT promoter activity. One of the novel associations (rs13174814) maps to a second region in the TERT promoter and the other (rs62329728) is in the promoter region of CLPTM1L; neither are correlated with previously reported cancer-associated SNPs. Using TCGA RNASeq data, we found significantly increased expression of both TERT and CLPTM1L in endometrial cancer tissue compared with normal tissue (TERTP¿=¿1.5¿×¿10-18, CLPTM1LP¿=¿1.5¿×¿10-19). Our study thus reports a novel endometrial cancer risk locus and expands the spectrum of cancer types associated with genetic variation at 5p15, further highlighting the importance of this region for cancer susceptibility.
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2015 |
Moscovis SM, Cox A, Hall ST, Burns CJ, Scott RJ, Blackwell CC, 'Effects of gender, cytokine gene polymorphisms and environmental factors on inflammatory responses', Innate Immunity, 21 523-530 (2015) [C1]
Previous studies have indicated that cytokine gene polymorphisms of Indigenous Australians were predominantly associated with strong pro-inflammatory responses. We tested the hypo... [more]
Previous studies have indicated that cytokine gene polymorphisms of Indigenous Australians were predominantly associated with strong pro-inflammatory responses. We tested the hypothesis that cells of donors with genetic profiles of inflammatory cytokine single nucleotide polymorphisms (SNPs) similar to Indigenous Australians produce higher pro-inflammatory responses. PBMCs from 14 donors with genetic profiles for a high risk of strong pro-inflammatory responses and 14 with low-risk profiles were stimulated with endotoxin and effects of gender, IFN-¿, cigarette smoke extract (CSE) and testosterone on cytokine responses analysed. Cytokines were calculated from standard curves (Luminex 2.3 software). No significant differences were associated with SNP profile alone. Lower pro-inflammatory responses were observed for cells from males with low- or high-risk profiles. For cells from females with high-risk profiles, anti-inflammatory IL-10 responses were significantly reduced. There was no effect of testosterone levels on responses from males. For females, results from IFN-¿-treated cells showed positive correlations between testosterone levels and IL-1ß responses to endotoxin for both risk groups and TNF-a for the high-risk group. If interactions observed among CSE, IFN-¿, genetic background and testosterone reflect those in vivo, these might contribute to increased incidences of hospitalisations for infectious diseases among Indigenous women.
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2015 |
Greenop KR, Bailey HD, Miller M, Scott RJ, Attia J, Ashton LJ, et al., 'Breastfeeding and nutrition to 2 years of age and risk of childhood acute lymphoblastic leukemia and brain tumors', Nutrition and Cancer, 67 431-441 (2015) [C1]
Acute lymphoblastic leukemia (ALL) and childhood brain tumors (CBT) are 2 of the most common forms of childhood cancer, but little is known of their etiology. In 2 nationwide case... [more]
Acute lymphoblastic leukemia (ALL) and childhood brain tumors (CBT) are 2 of the most common forms of childhood cancer, but little is known of their etiology. In 2 nationwide case-control studies we investigated whether breastfeeding, age of food introduction, or early diet are associated with the risk of these cancers. Cases aged 0-14 years were identified from Australian pediatric oncology units between 2003 and 2007 (ALL) and 2005 and 2010 (CBT) and population-based controls through nationwide random-digit dialing. Mothers completed questionnaires giving details of infant feeding up to the age of 2 yr. Data from 322 ALL cases, 679 ALL controls, 299 CBT cases, and 733 CBT controls were analysed using unconditional logistic regression. Breastfeeding was associated with a reduced risk of ALL [odds ratio (OR) = 0.52, 95% confidence interval (CI): 0.32, 0.84), regardless of duration. Introduction of artificial formula within 14 days of birth was positively associated with ALL (OR = 1.57, 95% CI: 1.03, 2.37), as was exclusive formula feeding to 6 mo (OR = 1.81, 95% CI: 1.07, 3.05). No associations were seen between breastfeeding or formula use and risk of CBT. Our results suggest that breastfeeding and delayed introduction of artificial formula may reduce the risk of ALL but not CBT.
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2015 |
Thompson ER, Gorringe KL, Rowley SM, Wong-Brown MW, McInerny S, Li N, et al., 'Prevalence of
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2015 |
O'Brien AR, Saunders NFW, Guo Y, Buske FA, Scott RJ, Bauer DC, 'VariantSpark: population scale clustering of genotype information.', BMC Genomics, 16 1052 (2015) [C1]
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2015 |
Chan JPL, Thalamuthu A, Oldmeadow C, Armstrong NJ, Holliday EG, McEvoy M, et al., 'Genetics of hand grip strength in mid to late life', Age, 37 1-10 (2015) [C1]
Hand grip strength (GS) is a predictor of mortality in older adults and is moderately to highly heritable, but no genetic variants have been consistently identified. We aimed to i... [more]
Hand grip strength (GS) is a predictor of mortality in older adults and is moderately to highly heritable, but no genetic variants have been consistently identified. We aimed to identify single nucleotide polymorphisms (SNPs) associated with GS in middle-aged to older adults using a genome-wide association study (GWAS). GS was measured using handheld dynamometry in community-dwelling men and women aged 55¿85 from the Hunter Community Study (HCS, N = 2088) and the Sydney Memory and Ageing Study (Sydney MAS, N = 541). Genotyping was undertaken using Affymetrix microarrays with imputation to HapMap2. Analyses were performed using linear regression. No genome-wide significant results were observed in HCS nor were any of the top signals replicated in Sydney MAS. Gene-based analyses in HCS identified two significant genes (ZNF295, C2CD2), but these results were not replicated in Sydney MAS. One out of eight SNPs previously associated with GS, rs550942, located near the CNTF gene, was significantly associated with GS (p = 0.005) in the HCS cohort only. Study differences may explain the lack of consistent results between the studies, including the smaller sample size of the Sydney MAS cohort. Our modest sample size also had limited power to identify variants of small effect. Our results suggest that similar to various other complex traits, many genetic variants of small effect size may influence GS. Future GWAS using larger samples and consistent measures may prove more fruitful at identifying genetic contributors for GS in middle-aged to older adults.
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2015 |
Greenop KR, Scott RJ, Attia J, Bower C, de Klerk NH, Norris MD, et al., 'Folate Pathway Gene Polymorphisms and Risk of Childhood Brain Tumors: Results from an Australian Case-Control Study', CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION, 24 931-937 (2015) [C1]
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2015 |
Maltby VE, Graves MC, Lea RA, Benton MC, Sanders KA, Tajouri L, et al., 'Genome-wide DNA methylation profiling of CD8+T cells shows a distinct epigenetic signature to CD4+T cells in multiple sclerosis patients', CLINICAL EPIGENETICS, 7 (2015) [C1]
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2015 |
Milne E, Greenop KR, Scott RJ, Haber M, Norris MD, Attia J, et al., 'Folate pathway gene polymorphisms, maternal folic acid use, and risk of childhood acute lymphoblastic leukemia', Cancer Epidemiology Biomarkers and Prevention, 24 48-56 (2015) [C1]
Background: Several studies suggest that maternal folic acid supplementation before or during pregnancy protects against childhood acute lymphoblastic leukemia (ALL). We investiga... [more]
Background: Several studies suggest that maternal folic acid supplementation before or during pregnancy protects against childhood acute lymphoblastic leukemia (ALL). We investigated associations between ALL risk and folate pathway gene polymorphisms, and their modification by maternal folic acid supplements, in a population-based case-control study (2003-2007). Methods: All Australian pediatric oncology centers provided cases; controls were recruited by national random digit dialing. Data from 392 cases and 535 controls were included. Seven folate pathway gene polymorphisms (MTHFR 677C>T, MTHFR 1298A>C, MTRR 66A>G, MTR 2756 A>G, MTR 5049 C>A, CBS 844 Ins68, and CBS 2199 T>C) were genotyped in children and their parents. Information on prepregnancy maternal folic acid supplement use was collected. ORs were estimated with unconditional logistic regression adjusted for frequency-matched variables and potential confounders. Case-parent trios were also analyzed. Results: There was some evidence of a reduced risk of ALL among children who had, or whose father had, the MTRR 66GG genotype: ORs 0.60 [95% confidence interval (CI) 0.39-0.91] and 0.64 (95% CI, 0.40-1.03), respectively. The ORs for paternal MTHFR 677CT and TT genotypes were 1.41 (95% CI, 1.02-1.93) and 1.81 (95% CI, 1.06-3.07). ORs varied little by maternal folic acid supplementation. Conclusions: Some folate pathway gene polymorphisms in the child or a parent may influence ALL risk. While biologically plausible, underlying mechanisms for these associations need further elucidation. Impact: Folate pathway polymorphisms may be related to risk of childhood ALL, but larger studies are needed for conclusive results.
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2015 |
Wong-Brown MW, Meldrum CJ, Carpenter JE, Clarke CL, Narod SA, Jakubowska A, et al., 'Prevalence of BRCA1 and BRCA2 germline mutations in patients with triple-negative breast cancer', Breast Cancer Research and Treatment, 150 71-80 (2015) [C1]
Triple-negative breast cancers¿(TNBC) lack expression of oestrogen, progesterone and HER2 receptors. The gene expression profiles of TNBCs are similar to those of breast tumours i... [more]
Triple-negative breast cancers¿(TNBC) lack expression of oestrogen, progesterone and HER2 receptors. The gene expression profiles of TNBCs are similar to those of breast tumours in women with BRCA1 mutations. Reports to date indicate that up to 20¿% of TNBC patients harbour germline BRCA mutations; however, the prevalence of BRCA mutations in TNBC patients varies widely between countries and from study to study. We studied 774 women with triple-negative breast cancer, diagnosed on average at age 58.0¿years. Samples of genomic DNA were provided by the Australian Breast Cancer Tissue Bank (ABCTB) (439 patients) and by the Department of Genetics and Pathology of the Pomeranian Medical University (335 patients). The entire coding regions and the exon¿intron boundaries of BRCA1 and BRCA2 were amplified and sequenced by next-generation sequencing. We identified a BRCA1 or BRCA2 mutation in 74 of 774 (9.6¿%) triple-negative patients. The mutation prevalence was 9.3¿% in Australia and was 9.9¿% in Poland. In both countries, the mean age of diagnoses of BRCA1 mutation carriers was significantly lower than that of non-carriers, while the age of onset of BRCA2 mutation carriers was similar to that of non-carriers. In the Australian cohort, 59¿% of the mutation-positive patients did not have a family history of breast or ovarian cancer, and would not have qualified for genetic testing. The triple-negative phenotype should be added as a criterion to genetic screening guidelines.
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2015 |
Davies G, Armstrong N, Bis JC, Bressler J, Chouraki V, Giddaluru S, et al., 'Genetic contributions to variation in general cognitive function: A meta-analysis of genome-wide association studies in the CHARGE consortium (N=53 949)', Molecular Psychiatry, 20 183-192 (2015) [C1]
General cognitive function is substantially heritable across the human life course from adolescence to old age. We investigated the genetic contribution to variation in this impor... [more]
General cognitive function is substantially heritable across the human life course from adolescence to old age. We investigated the genetic contribution to variation in this important, health- and well-being-related trait in middle-aged and older adults. We conducted a meta-analysis of genome-wide association studies of 31 cohorts (N=53 949) in which the participants had undertaken multiple, diverse cognitive tests. A general cognitive function phenotype was tested for, and created in each cohort by principal component analysis. We report 13 genome-wide significant single-nucleotide polymorphism (SNP) associations in three genomic regions, 6q16.1, 14q12 and 19q13.32 (best SNP and closest gene, respectively: rs10457441, P=3.93 × 10-9, MIR2113; rs17522122, P=2.55 × 10-8, AKAP6; rs10119, P=5.67 × 10-9, APOE/TOMM40). We report one gene-based significant association with the HMGN1 gene located on chromosome 21 (P=1 × 10-6). These genes have previously been associated with neuropsychiatric phenotypes. Meta-analysis results are consistent with a polygenic model of inheritance. To estimate SNP-based heritability, the genome-wide complex trait analysis procedure was applied to two large cohorts, the Atherosclerosis Risk in Communities Study (N=6617) and the Health and Retirement Study (N=5976). The proportion of phenotypic variation accounted for by all genotyped common SNPs was 29% (s.e.=5%) and 28% (s.e.=7%), respectively. Using polygenic prediction analysis, ~1.2% of the variance in general cognitive function was predicted in the Generation Scotland cohort (N=5487; P=1.5 × 10-17). In hypothesis-driven tests, there was significant association between general cognitive function and four genes previously associated with Alzheimer's disease: TOMM40, APOE, ABCG1 and MEF2C.
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2015 |
Sapkota Y, Attia J, Gordon SD, Henders AK, Holliday EG, Rahmioglu N, et al., 'Genetic burden associated with varying degrees of disease severity in endometriosis', MOLECULAR HUMAN REPRODUCTION, 21 594-602 (2015) [C1]
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2015 |
Greenop KR, Hinwood AL, Fritschi L, Scott RJ, Attia J, Ashton LJ, et al., 'Vehicle refuelling, use of domestic wood heaters and the risk of childhood brain tumours: Results from an Australian case-control study', Pediatric Blood and Cancer, 62 229-234 (2015) [C1]
The aetiology of childhood brain tumours (CBT) is largely unknown. Damage to germ cells after parental exposure to airborne carcinogens, such as volatile organic compounds and pol... [more]
The aetiology of childhood brain tumours (CBT) is largely unknown. Damage to germ cells after parental exposure to airborne carcinogens, such as volatile organic compounds and polycyclic aromatic hydrocarbons is one plausible pathway. This analysis aimed to investigate whether parental refuelling of vehicles or the use of domestic wood heaters in key time periods relating to the child's birth was associated with an increased risk of CBT. Procedure: Cases <15 years of age were recruited through 10 paediatric oncology centres around Australia; controls were recruited through nationwide random-digit dialling, frequency matched to cases on age, sex and State of residence. Exposure to refuelling and wood heaters was ascertained through questionnaires from both parents. Odds ratios (ORs) and confidence intervals (CIs) were estimated using unconditional logistic regression, adjusting for relevant covariates. Results: Data were available for 306 case and 950 control families. Paternal refuelling =4times/month was associated with an increased risk of CBT (OR 1.59, 95% CI: 1.11, 2.29), and a dose-dependent trend was observed (P=0.004). No association was seen for maternal refuelling. Use of closed, but not open, wood heaters before (OR 1.51, 95% CI: 1.05, 2.15) and after (OR 1.44, 95% CI: 1.03, 2.01) the child's birth was associated with increased risk of CBT, but dose-response relationships were weak or absent. Conclusions: Paternal refuelling of vehicles =4times/month and the use of closed wood heaters before the child's birth may increase the risk of CBT. Replication in larger studies is needed.
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2015 |
Debniak T, Gromowski T, Scott RJ, Gronwald J, Huzarski T, Byrski T, et al., 'Management of ovarian and endometrial cancers in women belonging to HNPCC carrier families: review of the literature and results of cancer risk assessment in Polish HNPCC families', HEREDITARY CANCER IN CLINICAL PRACTICE, 13 (2015) [C1]
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2015 |
Mathe A, Scott RJ, Avery-Kiejda KA, 'MiRNAs and other epigenetic changes as biomarkers in triple negative breast cancer', International Journal of Molecular Sciences, 16 28347-28376 (2015) [C1]
Triple negative breast cancer (TNBC) is characterised by the lack of receptors for estrogen (ER), progesterone (PR), and human epidermal growth factor 2 (HER2). Since it cannot be... [more]
Triple negative breast cancer (TNBC) is characterised by the lack of receptors for estrogen (ER), progesterone (PR), and human epidermal growth factor 2 (HER2). Since it cannot be treated by current endocrine therapies which target these receptors and due to its aggressive nature, it has one of the worst prognoses of all breast cancer subtypes. The only treatments remain chemo- and/or radio-therapy and surgery and because of this, novel biomarkers or treatment targets are urgently required to improve disease outcomes. MicroRNAs represent an attractive candidate for targeted therapies against TNBC, due to their natural ability to act as antisense interactors and regulators of entire gene sets involved in malignancy and their superiority over mRNA profiling to accurately classify disease. Here we review the current knowledge regarding miRNAs as biomarkers in TNBC and their potential use as therapeutic targets in this disease. Further, we review other epigenetic changes and interactions of these changes with microRNAs in this breast cancer subtype, which may lead to the discovery of new treatment targets for TNBC.
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2015 |
Pan X, Bowman M, Scott RJ, Fitter J, Nicholson RC, Smith R, Zakar T, 'Methylation of the Corticotropin Releasing Hormone Gene Promoter in BeWo Cells: Relationship to Gene Activity', International Journal of Endocrinology, 2015 (2015) [C1]
Corticotropin releasing hormone (CRH) production by the human placenta increases exponentially as pregnancy advances, and the rate of increase predicts gestational length. CRH gen... [more]
Corticotropin releasing hormone (CRH) production by the human placenta increases exponentially as pregnancy advances, and the rate of increase predicts gestational length. CRH gene expression is regulated by cAMP in trophoblasts through a cyclic AMP-response element (CRE), which changes its transcription factor binding properties upon methylation. Here we determined whether methylation of the CRH proximal promoter controls basal and cAMP-stimulated CRH expression in BeWo cells, a well-characterized trophoblastic cell line. We treated the cells with 8-Br-cAMP and the DNA methyltransferase inhibitor 5-aza-2' deoxycytidine (5-AZA-dC) and determined the effects on CRH mRNA level and promoter methylation. Clonal bisulfite sequencing showed partial and allele independent methylation of CpGs in the CRH promoter. CRH mRNA expression and the methylation of a subset of CpGs (including CpG2 in the CRE) increased spontaneously during culture. 8-Br-cAMP stimulated CRH expression without affecting the increase in methylation. 5-AZA-dC decreased methylation and augmented 8-Br-cAMP-stimulated CRH expression, but it blocked the spontaneous increase of CRH mRNA level. We conclude that the CRH promoter is a dynamically and intermediately methylated genomic region in BeWo cells. Promoter methylation did not inhibit CRH gene expression under the conditions employed; rather it determined the contribution of alternative cAMP-independent pathways and cAMP-independent mechanisms to CRH expression control.
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2015 |
Kamien B, Digilio MC, Novelli A, O'Donnell S, Bain N, Meldrum C, et al., 'Narrowing the critical region for overgrowth within 13q14.2-q14.3 microdeletions', European Journal of Medical Genetics, 58 629-633 (2015) [C3]
Large chromosomal deletions from 13q13.3 to 13q21.3 have previously been associated with overgrowth. We present two patients with deletions at 13q14.2q14.3 who have macrocephaly, ... [more]
Large chromosomal deletions from 13q13.3 to 13q21.3 have previously been associated with overgrowth. We present two patients with deletions at 13q14.2q14.3 who have macrocephaly, tall stature relative to their parents, cardiac phenotypes, and intellectual disability. This report narrows the critical region for tall stature, macrocephaly, and possibly cardiac disease. Crown
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2015 |
Paszkowska-Szczur K, Scott RJ, Górski B, Cybulski C, Kurzawski G, Dymerska D, et al., 'Polymorphisms in nucleotide excision repair genes and susceptibility to colorectal cancer in the Polish population', Molecular Biology Reports, 42 755-764 (2015) [C1]
Xeroderma pigmentosum (XP) is a rare autosomal recessive disease that is associated with a severe deficiency in nucleotide excision repair. Genetic polymorphisms in XP genes may b... [more]
Xeroderma pigmentosum (XP) is a rare autosomal recessive disease that is associated with a severe deficiency in nucleotide excision repair. Genetic polymorphisms in XP genes may be associated with a change in DNA repair capacity, which could be associated with colorectal cancer development. We assessed the association between 94 single nucleotide polymorphisms (SNPs) within seven XP genes (XPA¿XPG) and the colorectal cancer risk in the Polish population. We genotyped 758 unselected patients with colorectal cancer and 1,841 healthy adults. We found that a significantly decreased risk of colorectal cancer was associated with XPC polymorphism rs2228000_CT genotype (OR 0.59; p¿<¿0.0001) and the rs2228000_TT genotype (OR 0.29; p¿<¿0.0001) compared to the reference genotype (CC). And an increased disease risk was associated with the XPD SNP, rs1799793_AG genotype (OR 1.44, p¿=¿0.018) and rs1799793_AA genotype (OR 3.31, p¿<¿0.0001) compared to the reference genotype. Haplotype analysis within XPC, XPD and XPG revealed haplotypes associated with an altered colorectal cancer risk. Stratified analysis by gender showed differences between the association of three SNPs: XPC rs2228000, XPD rs1799793 and XPD rs238406 in females and males. Association analysis between age of disease onset and polymorphisms in XPD (rs1799793) and XPC (rs2228000) revealed differences in the prevalence of these variants in patients under and over 50¿years of age. Our results confirmed that polymorphisms in XPC and XPD may be associated with the risk of colorectal cancer.
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2015 |
Lener M, Muszynska M, Jakubowska A, Jaworska-Bieniek K, Sukiennicki G, Kaczmarek K, et al., 'Selenium as a marker of cancer risk and of selection for control examinations in surveillance', Wspolczesna Onkologia, 1A A60-A61 (2015)
Publication is summarization of existing data being results of literature review and our experience on usefulness of selenium as a diagnostic marker selection for control examinat... [more]
Publication is summarization of existing data being results of literature review and our experience on usefulness of selenium as a diagnostic marker selection for control examinations in surveillance and as a marker of patients with high risk of cancers.
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2015 |
Lubinski J, Scott RJ, Sijmons R, Bayliss K, 'Thank you to all our manuscript reviewers in 2014', Hereditary Cancer in Clinical Practice, 1-2 (2015) [O1]
© 2015 Lubinski et al.; licensee BioMed Central. The editors of Hereditary Cancer in Clinical Practice would like to thank all our reviewers who have contributed to the journal in... [more]
© 2015 Lubinski et al.; licensee BioMed Central. The editors of Hereditary Cancer in Clinical Practice would like to thank all our reviewers who have contributed to the journal in 2014. Without the participation of skilful reviewers, no academic journal could succeed, and we are grateful to the committed individuals who have given their time and expertise to the peer review of manuscripts for Hereditary Cancer in Clinical Practice. We look forward to your continued support in 2015.
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2015 |
Peyrot WJ, Lee SH, Milaneschi Y, Abdellaoui A, Byrne EM, Esko T, et al., 'The association between lower educational attainment and depression owing to shared genetic effects? Results in ~25 000 subjects', Molecular Psychiatry, 20 735-743 (2015) [C1]
An association between lower educational attainment (EA) and an increased risk for depression has been confirmed in various western countries. This study examines whether pleiotro... [more]
An association between lower educational attainment (EA) and an increased risk for depression has been confirmed in various western countries. This study examines whether pleiotropic genetic effects contribute to this association. Therefore, data were analyzed from a total of 9662 major depressive disorder (MDD) cases and 14 949 controls (with no lifetime MDD diagnosis) from the Psychiatric Genomics Consortium with additional Dutch and Estonian data. The association of EA and MDD was assessed with logistic regression in 15 138 individuals indicating a significantly negative association in our sample with an odds ratio for MDD 0.78 (0.75-0.82) per standard deviation increase in EA. With data of 884 105 autosomal common single-nucleotide polymorphisms (SNPs), three methods were applied to test for pleiotropy between MDD and EA: (i) genetic profile risk scores (GPRS) derived from training data for EA (independent meta-analysis on ~120 000 subjects) and MDD (using a 10-fold leave-one-out procedure in the current sample), (ii) bivariate genomic-relationship-matrix restricted maximum likelihood (GREML) and (iii) SNP effect concordance analysis (SECA). With these methods, we found (i) that the EA-GPRS did not predict MDD status, and MDD-GPRS did not predict EA, (ii) a weak negative genetic correlation with bivariate GREML analyses, but this correlation was not consistently significant, (iii) no evidence for concordance of MDD and EA SNP effects with SECA analysis. To conclude, our study confirms an association of lower EA and MDD risk, but this association was not because of measurable pleiotropic genetic effects, which suggests that environmental factors could be involved, for example, socioeconomic status.
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2015 |
Nead KT, Sharp SJ, Thompson DJ, Painter JN, Savage DB, Semple RK, et al., 'Evidence of a Causal Association Between Insulinemia and Endometrial Cancer: A Mendelian Randomization Analysis.', Journal of the National Cancer Institute, 107 djv178 (2015) [C1]
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2015 |
Bulik-Sullivan B, Loh PR, Finucane HK, Ripke S, Yang J, Patterson N, et al., 'LD score regression distinguishes confounding from polygenicity in genome-wide association studies', Nature Genetics, 47 291-295 (2015) [C1]
Both polygenicity (many small genetic effects) and confounding biases, such as cryptic relatedness and population stratification, can yield an inflated distribution of test statis... [more]
Both polygenicity (many small genetic effects) and confounding biases, such as cryptic relatedness and population stratification, can yield an inflated distribution of test statistics in genome-wide association studies (GWAS). However, current methods cannot distinguish between inflation from a true polygenic signal and bias. We have developed an approach, LD Score regression, that quantifies the contribution of each by examining the relationship between test statistics and linkage disequilibrium (LD). The LD Score regression intercept can be used to estimate a more powerful and accurate correction factor than genomic control. We find strong evidence that polygenicity accounts for the majority of the inflation in test statistics in many GWAS of large sample size.
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2015 |
Sobral-Leite M, Wesseling J, Smit VTHBM, Nevanlinna H, van Miltenburg MH, Sanders J, et al., 'Annexin A1 expression in a pooled breast cancer series: Association with tumor subtypes and prognosis', BMC Medicine, 13 (2015)
Background: Annexin A1 (ANXA1) is a protein related with the carcinogenesis process and metastasis formation in many tumors. However, little is known about the prognostic value of... [more]
Background: Annexin A1 (ANXA1) is a protein related with the carcinogenesis process and metastasis formation in many tumors. However, little is known about the prognostic value of ANXA1 in breast cancer. The purpose of this study is to evaluate the association between ANXA1 expression, BRCA1/2 germline carriership, specific tumor subtypes and survival in breast cancer patients. Methods: Clinical-pathological information and follow-up data were collected from nine breast cancer studies from the Breast Cancer Association Consortium (BCAC) (n = 5,752) and from one study of familial breast cancer patients with BRCA1/2 mutations (n = 107). ANXA1 expression was scored based on the percentage of immunohistochemical staining in tumor cells. Survival analyses were performed using a multivariable Cox model. Results: The frequency of ANXA1 positive tumors was higher in familial breast cancer patients with BRCA1/2 mutations than in BCAC patients, with 48.6% versus 12.4 %, respectively; P <0.0001. ANXA1 was also highly expressed in BCAC tumors that were poorly differentiated, triple negative, EGFR-CK5/6 positive or had developed in patients at a young age. In the first 5 years of follow-up, patients with ANXA1 positive tumors had a worse breast cancer-specific survival (BCSS) than ANXA1 negative (HRadj = 1.35; 95 % CI = 1.05-1.73), but the association weakened after 10 years (HRadj = 1.13; 95 % CI = 0.91-1.40). ANXA1 was a significant independent predictor of survival in HER2+ patients (10-years BCSS: HRadj = 1.70; 95 % CI = 1.17-2.45). Conclusions: ANXA1 is overexpressed in familial breast cancer patients with BRCA1/2 mutations and correlated with poor prognosis features: triple negative and poorly differentiated tumors. ANXA1 might be a biomarker candidate for breast cancer survival prediction in high risk groups such as HER2+ cases.
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2015 |
Bergon A, Belzeaux R, Comte M, Pelletier F, Hervé M, Gardiner EJ, et al., 'CX3CR1 is dysregulated in blood and brain from schizophrenia patients', Schizophrenia Research, 168 434-443 (2015) [C1]
The molecular mechanisms underlying schizophrenia remain largely unknown. Although schizophrenia is a mental disorder, there is increasing evidence to indicate that inflammatory p... [more]
The molecular mechanisms underlying schizophrenia remain largely unknown. Although schizophrenia is a mental disorder, there is increasing evidence to indicate that inflammatory processes driven by diverse environmental factors play a significant role in its development. With gene expression studies having been conducted across a variety of sample types, e.g., blood and postmortem brain, it is possible to investigate convergent signatures that may reveal interactions between the immune and nervous systems in schizophrenia pathophysiology. We conducted two meta-analyses of schizophrenia microarray gene expression data (N= 474) and non-psychiatric control (N= 485) data from postmortem brain and blood. Then, we assessed whether significantly dysregulated genes in schizophrenia could be shared between blood and brain. To validate our findings, we selected a top gene candidate and analyzed its expression by RT-qPCR in a cohort of schizophrenia subjects stabilized by atypical antipsychotic monotherapy (N= 29) and matched controls (N= 31). Meta-analyses highlighted inflammation as the major biological process associated with schizophrenia and that the chemokine receptor CX3CR1 was significantly down-regulated in schizophrenia. This differential expression was also confirmed in our validation cohort. Given both the recent data demonstrating selective CX3CR1 expression in subsets of neuroimmune cells, as well as behavioral and neuropathological observations of CX3CR1 deficiency in mouse models, our results of reduced CX3CR1 expression adds further support for a role played by monocyte/microglia in the neurodevelopment of schizophrenia.
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Nova |
2015 |
Green MJ, Raudino A, Cairns MJ, Wu J, Tooney PA, Scott RJ, Carr VJ, 'Do common genotypes of FK506 binding protein 5 (FKBP5) moderate the effects of childhood maltreatment on cognition in schizophrenia and healthy controls?', Journal of Psychiatric Research, 70 9-17 (2015) [C1]
Common variants of the FK506 binding protein 5 (FKBP5) gene are implicated in psychotic and other disorders, via their role in regulating glucocorticoid receptor (GR) receptor sen... [more]
Common variants of the FK506 binding protein 5 (FKBP5) gene are implicated in psychotic and other disorders, via their role in regulating glucocorticoid receptor (GR) receptor sensitivity and effects on the broader function of the HPA system in response to stress. In this study, the effects of four FKBP5 polymorphisms (rs1360780, rs9470080, rs4713902, rs9394309) on IQ and eight other cognitive domains were examined in the context of exposure to childhood maltreatment in 444 cases with schizophrenia and 292 healthy controls (from a total sample of 617 cases and 659 controls obtained from the Australian Schizophrenia Research Bank; ASRB). Participants subjected to any kind of maltreatment (including physical, emotional, or sexual abuse or physical or emotional neglect) in childhood were classified as 'exposed'; cognitive functioning was measured with Repeatable Battery for the Assessment of Neuropsychological Status, the Controlled Oral Word Association Test, and IQ was estimated with the Weschler Test of Adult Reading. Hierarchical regressions were used to test the main effects of genotype and childhood maltreatment, and their additive interactive effects, on cognitive function. For rs1360870, there were significant main effects of genotype and childhood maltreatment, and a significant interaction of genotype with childhood trauma affecting attention in both schizophrenia and healthy participants (C-homozygotes in both groups showed worse attention in the context of maltreatment); in SZ, this SNP also affected global neuropsychological function regardless of exposure to childhood trauma, with T-homozygotes showing worse cognition than other genotypes. The mechanisms of trauma-dependent effects of FKBP5 following early life trauma deserve further exploration in healthy and psychotic samples, in the context of epigenetic effects and perhaps epistasis with other genes. Study of these processes may be particularly informative in subgroups exposed to various other forms of early life adversity (i.e., birth complications, immigration).
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2015 |
Abdullah N, Abdul Murad NA, Attia J, Oldmeadow C, Mohd Haniff EA, Syafruddin SE, et al., 'Characterizing the genetic risk for Type 2 diabetes in a Malaysian multi-ethnic cohort.', Diabet Med, 32 1377-1384 (2015) [C1]
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2015 |
Darabi H, McCue K, Beesley J, Michailidou K, Nord S, Kar S, et al., 'Polymorphisms in a Putative Enhancer at the 10q21.2 Breast Cancer Risk Locus Regulate NRBF2 Expression', American Journal of Human Genetics, (2015) [C1]
Genome-wide association studies have identified SNPs near ZNF365 at 10q21.2 that are associated with both breast cancer risk and mammographic density. To identify the most likely ... [more]
Genome-wide association studies have identified SNPs near ZNF365 at 10q21.2 that are associated with both breast cancer risk and mammographic density. To identify the most likely causal SNPs, we fine mapped the association signal by genotyping 428 SNPs across the region in 89,050 European and 12,893 Asian case and control subjects from the Breast Cancer Association Consortium. We identified four independent sets of correlated, highly trait-associated variants (iCHAVs), three of which were located within ZNF365. The most strongly risk-associated SNP, rs10995201 in iCHAV1, showed clear evidence of association with both estrogen receptor (ER)-positive (OR = 0.85 [0.82-0.88]) and ER-negative (OR = 0.87 [0.82-0.91]) disease, and was also the SNP most strongly associated with percent mammographic density. iCHAV2 (lead SNP, chr10: 64,258,684:D) and iCHAV3 (lead SNP, rs7922449) were also associated with ER-positive (OR = 0.93 [0.91-0.95] and OR = 1.06 [1.03-1.09]) and ER-negative (OR = 0.95 [0.91-0.98] and OR = 1.08 [1.04-1.13]) disease. There was weaker evidence for iCHAV4, located 5' of ADO, associated only with ER-positive breast cancer (OR = 0.93 [0.90-0.96]). We found 12, 17, 18, and 2 candidate causal SNPs for breast cancer in iCHAVs 1-4, respectively. Chromosome conformation capture analysis showed that iCHAV2 interacts with the ZNF365 and NRBF2 (more than 600 kb away) promoters in normal and cancerous breast epithelial cells. Luciferase assays did not identify SNPs that affect transactivation of ZNF365, but identified a protective haplotype in iCHAV2, associated with silencing of the NRBF2 promoter, implicating this gene in the etiology of breast cancer.
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2015 |
Bowden NA, Beveridge NJ, Ashton KA, Baines KJ, Scott RJ, 'Understanding xeroderma pigmentosum complementation groups using gene expression profiling after UV-light exposure', International Journal of Molecular Sciences, 16 15985-15996 (2015) [C1]
Children with the recessive genetic disorder Xeroderma Pigmentosum (XP) have extreme sensitivity to UV-light, a 10,000-fold increase in skin cancers from age 2 and rarely live bey... [more]
Children with the recessive genetic disorder Xeroderma Pigmentosum (XP) have extreme sensitivity to UV-light, a 10,000-fold increase in skin cancers from age 2 and rarely live beyond 30 years. There are seven genetic subgroups of XP, which are all resultant of pathogenic mutations in genes in the nucleotide excision repair (NER) pathway and a XP variant resultant of a mutation in translesion synthesis, POLH. The clinical symptoms and severity of the disease is varied across the subgroups, which does not correlate with the functional position of the affected protein in the NER pathway. The aim of this study was to further understand the biology of XP subgroups, particularly those that manifest with neurological symptoms. Whole genome gene expression profiling of fibroblasts from each XP complementation group was assessed before and after UV-light exposure. The biological pathways with altered gene expression after UV-light exposure were distinct for each subtype and contained oncogenic related functions such as perturbation of cell cycle, apoptosis, proliferation and differentiation. Patients from the subgroups XP-B and XP-F were the only subgroups to have transcripts associated with neuronal activity altered after UV-light exposure. This study will assist in furthering our understanding of the different subtypes of XP which will lead to better diagnosis, treatment and management of the disease.
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Nova |
2015 |
Serrano-Fernandez P, Dymerska D, Kurzawski G, Derkacz R, Sobieszczanska T, Banaszkiewicz Z, et al., 'Cumulative Small Effect Genetic Markers and the Risk of Colorectal Cancer in Poland, Estonia, Lithuania, and Latvia', GASTROENTEROLOGY RESEARCH AND PRACTICE, 2015 (2015) [C1]
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Nova |
2015 |
Blackwell C, Moscovis S, Hall S, Burns C, Scott RJ, 'Exploring the risk factors for sudden infant deaths and their role in inflammatory responses to infection', Frontiers in Immunology, 6 (2015) [C1]
The risk factors for sudden infant death syndrome (SIDS) parallel those associated with susceptibility to or severity of infectious diseases. There is no evidence that a single in... [more]
The risk factors for sudden infant death syndrome (SIDS) parallel those associated with susceptibility to or severity of infectious diseases. There is no evidence that a single infectious agent is associated with SIDS; the common thread appears to be induction of inflammatory responses to infections. In this review, interactions between genetic and environmental risk factors for SIDS are assessed in relation to the hypothesis that many infant deaths result from dysregulation of inflammatory responses to "minor" infections. Risk factors are assessed in relation to three important stages of infection: (1) bacterial colonization (frequency or density); (2) induction of temperature-dependent toxins; (3) induction or control of inflammatory responses. In this article, we review the interactions among risk factors for SIDS for their effects on induction or control of inflammatory responses. The risk factors studied are genetic factors (sex, cytokine gene polymorphisms among ethnic groups at high or low risk of SIDS); developmental stage (changes in cortisol and testosterone levels associated with 2- to 4-month age range); environmental factors (virus infection, exposure to cigarette smoke). These interactions help to explain differences in the incidences of SIDS observed between ethnic groups prior to public health campaigns to reduce these infant deaths.
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Nova |
2015 |
Mavaddat N, Pharoah PDP, Michailidou K, Tyrer J, Brook MN, Bolla MK, et al., 'Prediction of breast cancer risk based on profiling with common genetic variants', Journal of the National Cancer Institute, 107 (2015) [C1]
Background: Data for multiple common susceptibility alleles for breast cancer may be combined to identify women at different levels of breast cancer risk. Such stratification coul... [more]
Background: Data for multiple common susceptibility alleles for breast cancer may be combined to identify women at different levels of breast cancer risk. Such stratification could guide preventive and screening strategies. However, empirical evidence for genetic risk stratification is lacking. Methods: We investigated the value of using 77 breast cancer-associated single nucleotide polymorphisms (SNPs) for risk stratification, in a study of 33 673 breast cancer cases and 33 381 control women of European origin. We tested all possible pair-wise multiplicative interactions and constructed a 77-SNP polygenic risk score (PRS) for breast cancer overall and by estrogen receptor (ER) status. Absolute risks of breast cancer by PRS were derived from relative risk estimates and UK incidence and mortality rates. Results: There was no strong evidence for departure from a multiplicative model for any SNP pair. Women in the highest 1% of the PRS had a three-fold increased risk of developing breast cancer compared with women in the middle quintile (odds ratio [OR] = 3.36, 95% confidence interval [CI] = 2.95 to 3.83). The ORs for ER-positive and ER-negative disease were 3.73 (95% CI = 3.24 to 4.30) and 2.80 (95% CI = 2.26 to 3.46), respectively. Lifetime risk of breast cancer for women in the lowest and highest quintiles of the PRS were 5.2% and 16.6% for a woman without family history, and 8.6% and 24.4% for a woman with a first-degree family history of breast cancer. Conclusions: The PRS stratifies breast cancer risk in women both with and without a family history of breast cancer. The observed level of risk discrimination could inform targeted screening and prevention strategies. Further discrimination may be achievable through combining the PRS with lifestyle/environmental factors, although these were not considered in this report.
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Nova |
2015 |
Movahedi M, Bishop DT, Macrae F, Mecklin JP, Moeslein G, Olschwang S, et al., 'Obesity, aspirin, and risk of colorectal cancer in carriers of hereditary colorectal cancer: A prospective investigation in the CAPP2 study', Journal of Clinical Oncology, 33 3591-3597 (2015) [C1]
Purpose: In the general population, increased adiposity is a significant risk factor for colorectal cancer (CRC), but whether obesity has similar effects in those with hereditary ... [more]
Purpose: In the general population, increased adiposity is a significant risk factor for colorectal cancer (CRC), but whether obesity has similar effects in those with hereditary CRC is uncertain. This prospective study investigated the association between body mass index and cancer risk in patients with Lynch syndrome (LS). Patients and Methods: Participants with LS were recruited to the CAPP2 study, in which they were randomly assigned to receive aspirin 600 mg per day or aspirin placebo, plus resistant starch 30 g per day or starch placebo (2×2 factorial design). Mean intervention period was 25.0 months, and mean follow-up was 55.7 months. Results: During follow-up, 55 of 937 participants developed CRC. For obese participants, CRC risk was 2.41 X (95% CI, 1.22 to 4.85) greater than for underweight and normal-weight participants (reference group), and CRC risk increased by 7% for each 1-kg/m2 increase in body mass index. The risk of all LS-related cancers in obese people was 1.77× (95% CI, 1.06 to 2.96; P = .03) greater than for the reference group. In subgroup analysis, obesity was associated with 3.72× (95% CI, 1.41 to 9.81) greater CRC risk in patients with LS with MLH1 mutation, but no excess risk was observed in those with MSH2 or MSH6 mutation (P = .5). The obesity-related excess CRC risk was confined to those randomly assigned to the aspirin placebo group (adjusted hazard ratio, 2.75; 95% CI, 1.12 to 6.79; P = .03). Conclusion: Obesity is associated with substantially increased CRC risk in patients with LS, but this risk is abrogated in those taking aspirin. Such patients are likely to benefit from obesity prevention and/or regular aspirin.
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Nova |
2015 |
Debette S, Ibrahim Verbaas CA, Bressler J, Schuur M, Smith A, Bis JC, et al., 'Genome-wide studies of verbal declarative memory in nondemented older people: The Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium', Biological Psychiatry, 77 749-763 (2015) [C1]
BACKGROUND: Memory performance in older persons can reflect genetic influences on cognitive function and dementing processes. We aimed to identify genetic contributions to verbal ... [more]
BACKGROUND: Memory performance in older persons can reflect genetic influences on cognitive function and dementing processes. We aimed to identify genetic contributions to verbal declarative memory in a community setting. METHODS: We conducted genome-wide association studies for paragraph or word list delayed recall in 19 cohorts from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, comprising 29,076 dementia- and stroke-free individuals of European descent, aged =45 years. Replication of suggestive associations (p < 5 × 10-6) was sought in 10,617 participants of European descent, 3811 African-Americans, and 1561 young adults. RESULTS: rs4420638, near APOE, was associated with poorer delayed recall performance in discovery (p = 5.57 × 10-10) and replication cohorts (p = 5.65 × 10-8). This association was stronger for paragraph than word list delayed recall and in the oldest persons. Two associations with specific tests, in subsets of the total sample, reached genome-wide significance in combined analyses of discovery and replication (rs11074779 [HS3ST4], p = 3.11 × 10-8, and rs6813517 [SPOCK3], p = 2.58 × 10-8) near genes involved in immune response. A genetic score combining 58 independent suggestive memory risk variants was associated with increasing Alzheimer disease pathology in 725 autopsy samples. Association of memory risk loci with gene expression in 138 human hippocampus samples showed cis-associations with WDR48 and CLDN5, both related to ubiquitin metabolism. CONCLUSIONS: This largest study to date exploring the genetics of memory function in ~40,000 older individuals revealed genome-wide associations and suggested an involvement of immune and ubiquitin pathways.
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Nova |
2015 |
Greenop KR, Miller M, Bailey HD, Scott RJ, Attia J, Bower C, et al., 'Paternal dietary folate, B6 and B12 intake, and the risk of childhood brain tumors', Nutrition and Cancer, 67 224-230 (2015) [C1]
It is biologically plausible that a paternal preconception diet low in nutrients related to DNA integrity could affect sperm DNA and subsequently risk of cancer in the offspring. ... [more]
It is biologically plausible that a paternal preconception diet low in nutrients related to DNA integrity could affect sperm DNA and subsequently risk of cancer in the offspring. The aim of this analysis was to investigate whether paternal preconception dietary folate, B6, or B12 intake was associated with the risk of childhood brain tumors (CBT) in an Australian case-control study. Cases <15 years of age were recruited from 10 Australian pediatric oncology centers between 2005 and 2010, and controls from random-digit dialing, frequency-matched to cases on age, sex, and state of residence. Paternal dietary information was obtained by food-frequency questionnaires. Nutrient values were energy adjusted and divided into tertiles for analysis by unconditional logistic regression. In fathers with relevant data (237 cases and 629 controls), no association with dietary folate and B6 and risk of CBT was seen; high B12 intake was associated with an increased risk of CBT (odds ratio highest vs. lowest tertile: 1.74, 95% confidence interval: 1.14, 2.66) without an increasing trend. These results do not support the hypothesis that paternal dietary folate intake influences the risk of CBT. The increased OR observed between dietary B12 intake and risk of CBT is without any certain explanation.
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Nova |
2015 |
Pundavela J, Roselli S, Faulkner S, Attia J, Scott RJ, Thorne RF, et al., 'Nerve fibers infiltrate the tumor microenvironment and are associated with nerve growth factor production and lymph node invasion in breast cancer', Molecular Oncology, 9 1626-1635 (2015) [C1]
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Nova |
2015 |
Garrison JR, Fernyhough C, McCarthy-Jones S, Haggard M, Carr V, Schall U, et al., 'Paracingulate sulcus morphology is associated with hallucinations in the human brain', Nature Communications, 6 (2015) [C1]
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Nova |
2015 |
Moir-Meyer GL, Pearson JF, Lose F, The Australian National Endometrial Cancer Study Group, Scott RJ, McEvoy M, et al., 'Rare germline copy number deletions of likely functional importance are implicated in endometrial cancer predisposition', Human Genetics, 134 269-278 (2015) [C1]
Endometrial cancer is the most common invasive gynaecological cancer in women, and relatively little is known about inherited risk factors for this disease. This is the first geno... [more]
Endometrial cancer is the most common invasive gynaecological cancer in women, and relatively little is known about inherited risk factors for this disease. This is the first genome-wide study to explore the role of common and rare germline copy number variants (CNVs) in predisposition to endometrial cancer. CNVs were called from germline DNA of 1,209 endometrioid endometrial cancer cases and 528 cancer-unaffected female controls. Overall CNV load of deletions or DNA gains did not differ significantly between cases and controls (P¿>¿0.05), but cases presented with an excess of rare germline deletions overlapping likely functional genomic regions including genes (P¿=¿8¿×¿10-10), CpG islands (P¿=¿1¿×¿10-7) and sno/miRNAs regions (P¿=¿3¿×¿10-9). On average, at least one additional gene and two additional CpG islands were disrupted by rare deletions in cases compared to controls. The most pronounced difference was that over 30 sno/miRNAs were disrupted by rare deletions in cases for every single disruption event in controls. A total of 13 DNA repair genes were disrupted by rare deletions in 19/1,209 cases (1.6¿%) compared to one gene in 1/528 controls (0.2¿%; P¿=¿0.007), and this increased DNA repair gene loss in cases persisted after excluding five individuals carrying CNVs disrupting mismatch repair genes MLH1, MSH2 and MSH6 (P¿=¿0.03). There were 34 miRNA regions deleted in at least one case but not in controls, the most frequent of which encompassed hsa-mir-661 and hsa-mir-203. Our study implicates rare germline deletions of functional and regulatory regions as possible mechanisms conferring endometrial cancer risk, and has identified specific regulatory elements as candidates for further investigation.
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Nova |
2015 |
Mathe A, Wong-Brown M, Morten B, Forbes JF, Braye SG, Avery-Kiejda KA, Scott RJ, 'Novel genes associated with lymph node metastasis in triple negative breast cancer', Scientific Reports, 5 (2015) [C1]
Triple negative breast cancer (TNBC) is the most aggressive breast cancer subtype with the worst prognosis and no targeted treatments. TNBC patients are more likely to develop met... [more]
Triple negative breast cancer (TNBC) is the most aggressive breast cancer subtype with the worst prognosis and no targeted treatments. TNBC patients are more likely to develop metastases and relapse than patients with other breast cancer subtypes. We aimed to identify TNBC-specific genes and genes associated with lymph node metastasis, one of the first signs of metastatic spread. A total of 33 TNBCs were used; 17 of which had matched normal adjacent tissues available, and 15 with matched lymph node metastases. Gene expression microarray analysis was used to reveal genes that were differentially expressed between these groups. We identified and validated 66 genes that are significantly altered when comparing tumours to normal adjacent samples. Further, we identified 83 genes that are associated with lymph node metastasis and correlated these with miRNA-expression. Pathway analysis revealed their involvement in DNA repair, recombination and cell death, chromosomal instability and other known cancer-related pathways. Finally, four genes were identified that were specific for TNBC, of which one was associated with overall survival. This study has identified novel genes involved in LN metastases in TNBC and genes that are TNBC specific that may be used as treatment targets or prognostic indicators in the future.
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Nova |
2015 |
Moscovis SM, Gordon AE, Al Madani OM, Gleeson M, Scott RJ, Hall ST, et al., 'Virus infections and sudden death in infancy: The role of interferon- ', Frontiers in Immunology, 6 (2015) [C1]
Respiratory infections have been implicated in sudden infant death syndrome (SIDS). As interferon-¿ (IFN-¿) is a major response to virus infection, we examined (1) the frequency o... [more]
Respiratory infections have been implicated in sudden infant death syndrome (SIDS). As interferon-¿ (IFN-¿) is a major response to virus infection, we examined (1) the frequency of single nucleotide polymorphism (SNP), IFNG T + 874A, in SIDS infants, their parents, and ethnic groups with different incidences of SIDS; (2) model systems with a monocytic cell line (THP-1) and human peripheral blood monocytes (PBMC) for effects of levels of IFN-¿ on inflammatory responses to bacterial antigens identified in SIDS; (3) interactions between genetic and environmental factors on IFN-¿ responses. IFNG T + 874A genotypes were determined for SIDS infants from three countries; families who had a SIDS death; populations with high (Indigenous Australian), medium (Caucasian), and low (Bangladeshi) SIDS incidences. The effect of IFN-¿ on cytokine responses to endotoxin was examined in model systems with THP-1 cells and human PBMC. The IFN-¿ responses to endotoxin and toxic shock syndrome toxin (TSST-1) were assessed in relation to genotype, gender, and reported smoking. There was a marginal association with IFNG T + 874A genotype and SIDS (p = 0.06). Indigenous Australians had significantly higher proportions of the IFNG T + 874A SNP (TT) associated with high responses of IFN-¿. THP-1 cells showed a dose dependent effect of IFN-¿ on cytokine responses to endotoxin. For PBMC, IFN-¿ enhanced interleukin (IL)-1ß, IL-6, and tumor necrosis factor-a responses but reduced IL-8 and IL-10 responses. Active smoking had a suppressive effect on baseline levels of IFN-¿. There was no effect of gender or genotype on IFN-¿ responses to bacterial antigens tested; however, significant differences were observed between genotypes in relation to smoking. The results indicate virus infections contribute to dysregulation of cytokine responses to bacterial antigens and studies on physiological effects of genetic factors must include controls for recent or concurrent infection and exposure to cigarette smoke.
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2015 |
Vilhjálmsson BJ, Yang J, Finucane HK, Gusev A, Lindström S, Ripke S, et al., 'Modeling Linkage Disequilibrium Increases Accuracy of Polygenic Risk Scores', American Journal of Human Genetics, 97 576-592 (2015) [C1]
Polygenic risk scores have shown great promise in predicting complex disease risk and will become more accurate as training sample sizes increase. The standard approach for calcul... [more]
Polygenic risk scores have shown great promise in predicting complex disease risk and will become more accurate as training sample sizes increase. The standard approach for calculating risk scores involves linkage disequilibrium (LD)-based marker pruning and applying a p value threshold to association statistics, but this discards information and can reduce predictive accuracy. We introduce LDpred, a method that infers the posterior mean effect size of each marker by using a prior on effect sizes and LD information from an external reference panel. Theory and simulations show that LDpred outperforms the approach of pruning followed by thresholding, particularly at large sample sizes. Accordingly, predicted R2 increased from 20.1% to 25.3% in a large schizophrenia dataset and from 9.8% to 12.0% in a large multiple sclerosis dataset. A similar relative improvement in accuracy was observed for three additional large disease datasets and for non-European schizophrenia samples. The advantage of LDpred over existing methods will grow as sample sizes increase.
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2015 |
Rush A, Christiansen JH, Farrell JP, Goode SM, Scott RJ, Spring KJ, Byrne JA, 'Biobank classification in an Australian setting', Biopreservation and Biobanking, 13 212-218 (2015) [C1]
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Nova |
2015 |
Painter JN, O'Mara TA, Batra J, Cheng T, Lose FA, Dennis J, et al., 'Fine-mapping of the
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Nova |
2015 |
Gu BJ, Field J, Dutertre S, Ou A, Kilpatrick TJ, Lechner-Scott J, et al., 'A rare P2X7 variant Arg307Gln with absent pore formation function protects against neuroinflammation in multiple sclerosis.', Human molecular genetics, 24 5644-5654 (2015) [C1]
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2015 |
Field J, Shahijanian F, Schibeci S, Johnson L, Gresle M, Laverick L, et al., 'The MS risk allele of CD40 is associated with reduced cell-membrane bound expression in antigen presenting cells: Implications for gene function', PLoS ONE, 10 (2015) [C1]
Human genetic and animal studies have implicated the costimulatory molecule CD40 in the development of multiple sclerosis (MS). We investigated the cell specific gene and protein ... [more]
Human genetic and animal studies have implicated the costimulatory molecule CD40 in the development of multiple sclerosis (MS). We investigated the cell specific gene and protein expression variation controlled by the CD40 genetic variant(s) associated with MS, i.e. the T-allele at rs1883832. Previously we had shown that the risk allele is expressed at a lower level in whole blood, especially in people with MS. Here, we have defined the immune cell subsets responsible for genotype and disease effects on CD40 expression at the mRNA and protein level. In cell subsets in which CD40 is most highly expressed, B lymphocytes and dendritic cells, the MS-associated risk variant is associated with reduced CD40 cell-surface protein expression. In monocytes and dendritic cells, the risk allele additionally reduces the ratio of expression of full-length versus truncated CD40 mRNA, the latter encoding secreted CD40. We additionally show that MS patients, regardless of genotype, express significantly lower levels of CD40 cell-surface protein compared to unaffected controls in B lymphocytes. Thus, both genotype-dependent and independent down-regulation of cell-surface CD40 is a feature of MS. Lower expression of a co-stimulator of T cell activation, CD40, is therefore associated with increased MS risk despite the same CD40 variant being associated with reduced risk of other inflammatory autoimmune diseases. Our results highlight the complexity and likely individuality of autoimmune pathogenesis, and could be consistent with antiviral and/or immunoregulatory functions of CD40 playing an important role in protection from MS.
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2015 |
Hancock DB, Levy JL, Gaddis NC, Glasheen C, Saccone NL, Page GP, et al., 'Cis-Expression Quantitative Trait Loci Mapping Reveals Replicable Associations with Heroin Addiction in OPRM1', Biological Psychiatry, 78 474-484 (2015) [C1]
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Nova |
2015 |
Holliday EG, Traylor M, Malik R, Bevan S, Falcone G, Hopewell JC, et al., 'Genetic Overlap Between Diagnostic Subtypes of Ischemic Stroke', STROKE, 46 615-+ (2015) [C1]
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Nova |
2015 |
Sapkota Y, Low SK, Attia J, Gordon SD, Henders AK, Holliday EG, et al., 'Association between endometriosis and the interleukin 1A (IL1A) locus.', Human Reproduction, 30 239-248 (2015) [C1]
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Nova |
2015 |
Finucane HK, Bulik-Sullivan B, Gusev A, Trynka G, Reshef Y, Loh P-R, et al., 'Partitioning heritability by functional annotation using genome-wide association summary statistics', Nature Genetics, 47 1228-1235 (2015) [C1]
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Nova |
2015 |
Loh P-R, Bhatia G, Gusev A, Finucane HK, Bulik-Sullivan BK, Pollack SJ, et al., 'Contrasting genetic architectures of schizophrenia and other complex diseases using fast variance-components analysis', Nature Genetics, 47 1385-1392 (2015) [C1]
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Nova |
2015 |
O'Mara TA, Glubb DM, Painter JN, Cheng T, Dennis J, Australian National Endometrial Cancer Study Group (ANECS), et al., 'Comprehensive genetic assessment of the ESR1 locus identifies a risk region for endometrial cancer.', Endocr Relat Cancer, 22 851-861 (2015) [C1]
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Nova |
2015 |
Ingason A, Giegling I, Hartmann AM, Genius J, Konte B, Friedl M, et al., 'Expression analysis in a rat psychosis model identifies novel candidate genes validated in a large case control sample of schizophrenia', Translational Psychiatry, 5 e656-e656 [C1]
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Nova |
2015 |
Thompson ER, Gorringe KL, Rowley SM, Li N, McInerny S, Wong-Brown MW, et al., 'Reevaluation of the
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Nova |
2015 |
Cropley VL, Scarr E, Fornito A, Klauser P, Bousman CA, Scott R, et al., 'The effect of a muscarinic receptor 1 gene variant on grey matter volume in schizophrenia', Psychiatry Research - Neuroimaging, 234 182-187 (2015) [C1]
Previous research has demonstrated that individuals with schizophrenia who are homozygous at the c.267C>A single nucleotide polymorphism (rs2067477) within the cholinergic musc... [more]
Previous research has demonstrated that individuals with schizophrenia who are homozygous at the c.267C>A single nucleotide polymorphism (rs2067477) within the cholinergic muscarinic M1 receptor (CHRM1) perform less well on the Wisconsin Card Sorting Test (WCST) than those who are heterozygous. This study sought to determine whether variation in the rs2067477 genotype was associated with differential changes in brain structure. Data from 227 patients with established schizophrenia or schizoaffective disorder were obtained from the Australian Schizophrenia Research Bank. Whole-brain voxel-based morphometry was performed to compare regional grey matter volume (GMV) between the 267C/C (N=191) and 267C/A (N=36) groups. Secondary analyses tested for an effect of genotype on cognition (the WCST was not available). Individuals who were homozygous (267C/C) demonstrated significantly reduced GMV in the right precentral gyrus compared to those who were heterozygous (267C/A). These preliminary results suggest that the rs2067477 genotype is associated with brain structure in the right precentral gyrus in individuals with schizophrenia/schizoaffective disorder. Future studies are required to replicate these results and directly link the volumetric reductions with specific cognitive processes.
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Nova |
2014 |
Oldmeadow C, Mossman D, Evans T-J, Holliday EG, Tooney PA, Cairns MJ, et al., 'Combined analysis of exon splicing and genome wide polymorphism data predict schizophrenia risk loci.', J Psychiatr Res, 52 44-49 (2014) [C1]
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Nova |
2014 |
Evans T-J, Milne E, Anderson D, de Klerk NH, Jamieson SE, Talseth-Palmer BA, et al., 'Confirmation of childhood acute lymphoblastic leukemia variants, ARID5B and IKZF1, and interaction with parental environmental exposures.', PLoS One, 9 e110255 (2014) [C1]
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Nova |
2014 |
Hysi PG, Cheng C-Y, Springelkamp H, Macgregor S, Bailey JNC, Wojciechowski R, et al., 'Genome-wide analysis of multi-ancestry cohorts identifies new loci influencing intraocular pressure and susceptibility to glaucoma', NATURE GENETICS, 46 1126-1130 (2014)
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2014 |
Avery-Kiejda KA, Braye SG, Forbes JF, Scott RJ, 'The expression of Dicer and Drosha in matched normal tissues, tumours and lymph node metastases in triple negative breast cancer', BMC CANCER, 14 (2014) [C1]
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Nova |
2014 |
Gusev A, Lee SH, Trynka G, Finucane H, Vilhjálmsson BJ, Xu H, et al., 'Partitioning Heritability of Regulatory and Cell-Type-Specific Variants across 11 Common Diseases', The American Journal of Human Genetics, 95 535-552 (2014) [C1]
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Nova |
2014 |
Nicodemus KK, Hargreaves A, Morris D, Anney R, Gill M, Corvin A, Donohoe G, 'Variability in Working Memory Performance Explained by Epistasis vs Polygenic Scores in the
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Nova |
2014 |
Graves MC, Benton M, Lea RA, Boyle M, Tajouri L, Macartney-Coxson D, et al., 'Methylation differences at the HLA-DRB1 locus in CD4+ T-Cells are associated with multiple sclerosis', Multiple Sclerosis Journal, 20 1033-1041 (2014) [C1]
Background: Multiple sclerosis (MS) is thought to be caused by T-cell mediated autoimmune dysfunction. Risk ofdeveloping MS is influenced by environmental and genetic factors. Mod... [more]
Background: Multiple sclerosis (MS) is thought to be caused by T-cell mediated autoimmune dysfunction. Risk ofdeveloping MS is influenced by environmental and genetic factors. Modifiable differences in DNA methylation arerecognized as epigenetic contributors to MS risk and may provide a valuable link between environmental exposure andinherited genetic systems.Objectives and methods: To identify methylation changes associated with MS, we performed a genome-wide DNAmethylation analysis of CD4+ T cells from 30 patients with relapsing-remitting MS and 28 healthy controls using Illumina450K methylation arrays.Results: A striking differential methylation signal was observed at chr. 6p21, with a peak signal at HLA-DRB1. Afterprioritisation, we identified a panel of 74 CpGs associated with MS in this cohort. Most notably we found evidence of amajor effect CpG island in DRB1 in MS cases (pFDR <3 x 10<sup>-3</sup>). In addition, we found 55 non-HLA CpGs that exhibiteddifferential methylation, many of which localise to genes previously linked to MS.Conclusions: Our findings provide the first evidence for association of DNA methylation at HLA-DRB1 in relation toMS risk. Further studies are now warranted to validate and understand how these findings are involved in MS pathology. © The Author(s) 2013.
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Nova |
2014 |
Dymerska D, Kurzawski G, Suchy J, Roomere H, Toome K, Metspalu A, et al., 'Lynch syndrome mutations shared by the Baltic States and Poland', Clinical Genetics, 86 190-193 (2014) [C3]
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2014 |
Holliday EG, Attia J, Hancock S, Koloski N, McEvoy M, Peel R, et al., 'Genome-wide association study identifies two novel genomic regions in irritable bowel syndrome', American Journal of Gastroenterology, 109 770-772 (2014) [C1]
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Nova |
2014 |
Wong-Brown MW, Avery-Kiejda KA, Bowden NA, Scott RJ, 'Low prevalence of germline PALB2 mutations in Australian triple-negative breast cancer', International Journal of Cancer, 134 301-305 (2014) [C1]
Triple-negative breast cancer (TNBC) is a tumour classification that is defined by oestrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 receptor ... [more]
Triple-negative breast cancer (TNBC) is a tumour classification that is defined by oestrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 receptor negativity. TNBCs share a similar gene expression profile to BRCA-mutated tumours, have been shown to carry a high proportion of BRCA mutations and have a more adverse prognosis compared to other types of breast tumours. PALB2 has been shown to be a moderate-penetrance breast cancer susceptibility gene and is involved in the same DNA damage repair pathway as BRCA1 and BRCA2; this raises the possibility that germline PALB2 mutations may be involved in the pathogenesis of TNBCs. In our study, we sequenced the coding regions of PALB2 (including intron/exon boundaries) in genomic DNA from 347 patients diagnosed with TNBC to determine the prevalence of deleterious mutations in this population. Two novel truncating mutations (c.758dup and c.2390del) and one previously detected truncating mutation (c.3113+5G>C) were found. In addition, five variants predicted to be protein-affecting were also identified. Our study shows that the prevalence of PALB2 germline mutations in individuals with TNBC is ~1%, similar to the prevalence of PALB2 germline mutation of 1% in familial non-BRCA1/2 breast cancer cohorts. © 2013 UICC.
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Nova |
2014 |
McCarthy-Jones S, Green MJ, Scott RJ, Tooney PA, Cairns MJ, Wu JQ, et al., 'Preliminary evidence of an interaction between the
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Nova |
2014 |
Green MJ, Chia TY, Cairns MJ, Wu J, Tooney PA, Scott RJ, Carr VJ, 'Catechol-O-methyltransferase (COMT) genotype moderates the effects of childhood trauma on cognition and symptoms in schizophrenia', Journal of Psychiatric Research, 49 43-50 (2014) [C1]
The interaction of genetic and environmental factors may affect the course and development of psychotic disorders. We examined whether the effects of childhood trauma on cognition... [more]
The interaction of genetic and environmental factors may affect the course and development of psychotic disorders. We examined whether the effects of childhood trauma on cognition and symptoms in schizophrenia were moderated by the Catechol-O-methyltransferase (COMT) Val158Met polymorphism, a common genetic variant known to affect cognition and prefrontal dopamine levels. Participants were 429 schizophrenia/schizoaffective cases from the Australian Schizophrenia Research Bank (ASRB). Cognitive performance was assessed using the Repeatable Battery for Assessment of Neuropsychological Status (RBANS), Controlled Oral Word Association Test (COWAT), Letter Number Sequencing (LNS) test, and the Wechsler Test of Adult Reading (WTAR). Hierarchical regression was used to test the main effects and additive interaction effects of genotype and childhood trauma in the domains of physical abuse, emotional abuse, and emotional neglect, on cognition and symptom profiles of clinical cases. Consistent with previous findings, COMT Val homozygotes performed worse on cognitive measures in the absence of childhood adversity. In addition, a significant interaction between COMT genotype and physical abuse was associated with better executive function in Val homozygotes, relative to those of the same genotype with no history of abuse. Finally, the severity of positive symptoms was greater in Met carriers who had experienced physical abuse, and the severity of negative symptoms in Met carriers was greater in the presence of emotional neglect. These results suggest that the possible epigenetic modulation of the expression of the COMT Val158Met polymorphism and consequent effects on cognition and symptoms in schizophrenia, with worse outcomes associated with adverse childhood experiences in Met carriers. © 2013 Elsevier Ltd.
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Nova |
2014 |
Ripke S, Neale BM, Corvin A, Walters JTR, Farh KH, Holmans PA, et al., 'Biological insights from 108 schizophrenia-associated genetic loci', Nature, 511 421-427 (2014) [C1]
Schizophrenia is a highly heritable disorder. Genetic risk is conferred by a large number of alleles, including common alleles of small effect that might be detected by genome-wid... [more]
Schizophrenia is a highly heritable disorder. Genetic risk is conferred by a large number of alleles, including common alleles of small effect that might be detected by genome-wide association studies. Here we report a multi-stage schizophrenia genome-wide association study of up to 36,989 cases and 113,075 controls. We identify 128 independent associations spanning 108 conservatively defined loci that meet genome-wide significance, 83 of which have not been previously reported. Associations were enriched among genes expressed in brain, providing biological plausibility for the findings. Many findings have the potential to provide entirely new insights into aetiology, but associations at DRD2 and several genes involved in glutamatergic neurotransmission highlight molecules of known and potential therapeutic relevance to schizophrenia, and are consistent with leading pathophysiological hypotheses. Independent of genes expressed in brain, associations were enriched among genes expressed in tissues that have important roles in immunity, providing support for the speculated link between the immune system and schizophrenia. © 2014 Macmillan Publishers Limited. All rights reserved.
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Nova |
2014 |
Pluschke A, Jaaback K, Scott RJ, Lombard J, Yin H, 'Epithelioid trophoblastic tumour simulating a high grade carcinoma', PATHOLOGY, 46 248-250 (2014) [C3]
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2014 |
Greenop KR, de Klerk NH, Bower C, Milne E, Miller M, Scott RJ, et al., 'Maternal Dietary Intake of Folate and Vitamins B6 and B12 During Pregnancy and Risk of Childhood Brain Tumors', Nutrition and Cancer, (2014) [C1]
Childhood brain tumors (CBT) are the second most common childhood cancers, yet their etiology is largely unknown. We investigated whether maternal gestational intake of folate and... [more]
Childhood brain tumors (CBT) are the second most common childhood cancers, yet their etiology is largely unknown. We investigated whether maternal gestational intake of folate and vitamins B6 and B12 was associated with CBT risk in a nationwide case-control study conducted 2005-2010. Case children 0-14 years were recruited from all 10 Australian pediatric oncology centers. Control children were recruited by national random digit dialing, frequency matched to cases on age, sex, and state of residence. Dietary intake was ascertained using food frequency questionnaires and adjusted for total energy intake. Data from 293 case and 726 control mothers were analyzed using unconditional logistic regression. The odds ratio (OR) for the highest versus lowest tertile of folate intake was 0.70 [95% confidence interval (CI): 0.48, 1.02]. The ORs appeared lower in mothers who drank alcohol during pregnancy (OR = 0.45, 95% CI: 0.22, 0.93), mothers who took folic acid (OR = 0.67, 95% CI: 0.42, 1.06) or B6/B12 supplements (OR = 0.51, 95% CI: 0.25, 1.06) and in children younger than 5 years (OR = 0.50, 95% CI: 0.27, 0.93). These findings are consistent with folate's crucial role in maintenance of genomic integrity and DNA methylation. Dietary intake of B6 and B12 was not associated with risk of CBT. © 2014 Copyright © Taylor & Francis Group, LLC.
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Nova |
2014 |
De Vivo I, Prescott J, Setiawan VW, Olson SH, Wentzensen N, Attia J, et al., 'Genome-wide association study of endometrial cancer in E2C2', HUMAN GENETICS, 133 211-224 (2014) [C1]
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Nova |
2014 |
Williams FMK, Carter AM, Hysi PG, Surdulescu G, Hodgkiss D, Soranzo N, et al., 'Ischemic stroke is associated with the ABO locus: The EuroCLOT study (vol 73, pg 16, 2013)', ANNALS OF NEUROLOGY, 75 166-167 (2014)
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2014 |
Mirecka A, Paszkowska-Szczur K, Scott RJ, Górski B, van de Wetering T, Wokolorczyk D, et al., 'Common variants of xeroderma pigmentosum genes and prostate cancer risk', Gene, 546 156-161 (2014) [C1]
The genetic basis of prostate cancer (PC) is complex and appears to involve multiple susceptibility genes. A number of studies have evaluated a possible correlation between severa... [more]
The genetic basis of prostate cancer (PC) is complex and appears to involve multiple susceptibility genes. A number of studies have evaluated a possible correlation between several NER gene polymorphisms and PC risk, but most of them evaluated only single SNPs among XP genes and the results remain inconsistent. Out of 94 SNPs located in seven XP genes (XPA-. XPG) a total of 15 SNPs were assayed in 720 unselected patients with PC and compared to 1121 healthy adults. An increased risk of disease was associated with the XPD SNP, rs1799793 (Asp312Asn) AG genotype (OR. = 2.60; p. <. 0.001) and with the AA genotype (OR. = 531; p. <. 0.0001) compared to the control population. Haplotype analysis of XPD revealed one protective haplotype and four associated with an increased disease risk, which showed that the A allele (XPD rs1799793) appeared to drive the main effect on promoting prostate cancer risk. Polymorphism in XPD gene appears to be associated with the risk of prostate cancer. © 2014.
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Nova |
2014 |
Greenop KR, Peters S, Fritschi L, Glass DC, Ashton LJ, Bailey HD, et al., 'Exposure to household painting and floor treatments, and parental occupational paint exposure and risk of childhood brain tumors: results from an Australian case-control study', CANCER CAUSES & CONTROL, 25 283-291 (2014) [C1]
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Nova |
2014 |
Greenop KR, Peters S, Bailey HD, Fritschi L, Attia J, Scott RJ, et al., 'Exposure to pesticides and the risk of childhood brain tumors (vol 24, pg 1269, 2013)', CANCER CAUSES & CONTROL, 25 1239-1240 (2014) [O1]
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2014 |
Greenop KR, Peters S, Fritschi L, Glass DC, Ashton LJ, Bailey HD, et al., 'Erratum to: Exposure to household painting and floor treatments, and parental occupational paint exposure and risk of childhood brain tumors: results from an Australian case-control study', Cancer Causes & Control, (2014) [O1]
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2014 |
Milne E, Greenop KR, Fritschi L, Attia J, Bailey HD, Scott RJ, et al., 'Childhood and parental diagnostic radiological procedures and risk of childhood brain tumors', Cancer Causes and Control, 25 375-383 (2014) [C1]
Purpose: Childhood brain tumors (CBT) are the second most common type of childhood cancer and the leading cause of childhood cancer mortality. Few causes of CBT are known, but par... [more]
Purpose: Childhood brain tumors (CBT) are the second most common type of childhood cancer and the leading cause of childhood cancer mortality. Few causes of CBT are known, but parental, fetal, and early life exposures are likely to be important given the early age at diagnosis of many cases. We aimed to investigate whether parents' diagnostic radiological procedures before conception, in the mother during pregnancy or the child's procedures were associated with an increased risk of CBT. Methods: This population-based case-control study was conducted between 2005 and 2010. Cases were identified through all ten Australian pediatric oncology centers, and controls via nationwide random-digit dialing; frequency-matched to cases on age, sex and state of residence. Information on radiological exposures in the time periods of interest was obtained for 306 case and 950 control families through mailed questionnaires. Analysis used unconditional logistic regression, adjusting for matching variables and potential confounders. Results: We found no evidence of positive associations between risk of CBT overall and childhood or parental pre-pregnancy radiological procedures. Increased ORs for high-grade gliomas associated with childhood radiological procedures were based on small numbers and may be due to chance. Conclusions: Given the evidence for an increased risk of CBT in cohort studies of computed tomography (CT) in childhood, the lack of such an association in our study may be due to the reduced intensity of CTs after 2001. Future research to investigate the safety of fetal exposure to more intense procedures like CT scans is needed. © 2014 Springer International Publishing Switzerland.
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Nova |
2014 |
Moayyeri A, Hsu Y-H, Karasik D, Estrada K, Xiao S-M, Nielson C, et al., 'Genetic determinants of heel bone properties: genome-wide association meta-analysis and replication in the GEFOS/GENOMOS consortium', HUMAN MOLECULAR GENETICS, 23 3054-3068 (2014) [C1]
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Nova |
2014 |
Purrington KS, Slettedahl S, Bolla MK, Michailidou K, Czene K, Nevanlinna H, et al., 'Genetic variation in mitotic regulatory pathway genes is associated with breast tumor grade', HUMAN MOLECULAR GENETICS, 23 6034-6046 (2014) [C1]
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Nova |
2014 |
Springelkamp H, Höhn R, Mishra A, Hysi PG, Khor CC, Loomis SJ, et al., 'Meta-analysis of genome-wide association studies identifies novel loci that influence cupping and the glaucomatous process', Nature Communications, 5 (2014) [C1]
Glaucoma is characterized by irreversible optic nerve degeneration and is the most frequent cause of irreversible blindness worldwide. Here, the International Glaucoma Genetics Co... [more]
Glaucoma is characterized by irreversible optic nerve degeneration and is the most frequent cause of irreversible blindness worldwide. Here, the International Glaucoma Genetics Consortium conducts a meta-analysis of genome-wide association studies of vertical cup-disc ratio (VCDR), an important disease-related optic nerve parameter. In 21,094 individuals of European ancestry and 6,784 individuals of Asian ancestry, we identify 10 new loci associated with variation in VCDR. In a separate risk-score analysis of five case-control studies, Caucasians in the highest quintile have a 2.5-fold increased risk of primary open-angle glaucoma as compared with those in the lowest quintile. This study has more than doubled the known loci associated with optic disc cupping and will allow greater understanding of mechanisms involved in this common blinding condition.
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Nova |
2014 |
Wan C, Latter JL, Amirshahi A, Symonds I, Finnie J, Bowden N, et al., 'Progesterone Activates Multiple Innate Immune Pathways in Chlamydia trachomatis-Infected Endocervical Cells', American Journal of Reproductive Immunology, 71 165-177 (2014) [C1]
Problem: Susceptibility to Chlamydia trachomatis infection is increased by oral contraceptives and modulated by sex hormones. We therefore sought to determine the effects of femal... [more]
Problem: Susceptibility to Chlamydia trachomatis infection is increased by oral contraceptives and modulated by sex hormones. We therefore sought to determine the effects of female sex hormones on the innate immune response to C. trachomatis infection. Method of study: ECC-1 endometrial cells, pre-treated with oestradiol or progesterone, were infected with C. trachomatis and the host transcriptome analysed by Illumina Sentrix HumanRef-8 microarray. Primary endocervical epithelial cells, prepared at either the proliferative or secretory phase of the menstrual cycle, were infected with C. trachomatis and cytokine gene expression determined by quantitative RT-PCR analysis. Results: Chlamydia trachomatis yield from progesterone-primed ECC-1 cells was significantly reduced compared with oestradiol-treated cells. Genes upregulated in progesterone-treated and Chlamydia-infected cells only included multiple CC and CXC chemokines, IL-17C, IL-29, IL-32, TNF-a, DEFB4B, LCN2, S100A7-9, ITGAM, NOD2, JAK1, IL-6ST, type I and II interferon receptors, numerous interferon-stimulated genes and STAT6. CXCL10, CXCL11, CX3CL1 and IL-17C, which were also upregulated in infected secretory-stage primary cells, and there was a trend towards higher levels of immune mediators in infected secretory-phase compared with proliferative-phase cells. Conclusion: Progesterone treatment primes multiple innate immune pathways in hormone-responsive epithelial cells that could potentially increase resistance to chlamydial infection. © 2013 John Wiley & Sons Ltd.
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Nova |
2014 |
Loth DW, Artigas MS, Gharib SA, Wain LV, Franceschini N, Koch B, et al., 'Genome-wide association analysis identifies six new loci associated with forced vital capacity', NATURE GENETICS, 46 669-677 (2014) [C1]
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Nova |
2014 |
Thompson BA, Spurdle AB, Plazzer JP, Greenblatt MS, Akagi K, Al-Mulla F, et al., 'Application of a 5-tiered scheme for standardized classification of 2,360 unique mismatch repair gene variants in the InSiGHT locus-specific database', Nature Genetics, 46 107-115 (2014) [C1]
The clinical classification of hereditary sequence variants identified in disease-related genes directly affects clinical management of patients and their relatives. The Internati... [more]
The clinical classification of hereditary sequence variants identified in disease-related genes directly affects clinical management of patients and their relatives. The International Society for Gastrointestinal Hereditary Tumours (InSiGHT) undertook a collaborative effort to develop, test and apply a standardized classification scheme to constitutional variants in the Lynch syndrome-associated genes MLH1, MSH2, MSH6 and PMS2. Unpublished data submission was encouraged to assist in variant classification and was recognized through microattribution. The scheme was refined by multidisciplinary expert committee review of the clinical and functional data available for variants, applied to 2,360 sequence alterations, and disseminated online. Assessment using validated criteria altered classifications for 66% of 12,006 database entries. Clinical recommendations based on transparent evaluation are now possible for 1,370 variants that were not obviously protein truncating from nomenclature. This large-scale endeavor will facilitate the consistent management of families suspected to have Lynch syndrome and demonstrates the value of multidisciplinary collaboration in the curation and classification of variants in public locus-specific databases. © 2014 Nature America, Inc.
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Nova |
2014 |
Holliday EG, Traylor M, Malik R, Bevan S, Maguire J, Koblar SA, et al., 'Polygenic Overlap Between Kidney Function and Large Artery Atherosclerotic Stroke', STROKE, 45 3508-+ (2014) [C1]
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Nova |
2014 |
Cox MB, Bowden NA, Scott RJ, Lechner-Scott J, 'Common genetic variants in the plasminogen activation pathway are not associated with multiple sclerosis', Multiple Sclerosis Journal, 20 489-491 (2014) [C1]
Matrix metalloproteinase 9 (MMP9) is involved in multiple sclerosis (MS) aetiology. Previously, we identified differential gene expression of plasminogen activation cascade genes ... [more]
Matrix metalloproteinase 9 (MMP9) is involved in multiple sclerosis (MS) aetiology. Previously, we identified differential gene expression of plasminogen activation cascade genes in MS patients. Based on our gene expression results, we wanted to identify whether polymorphisms in the genes associated with the plasminogen pathway could predict MS risk. We genotyped 1153 trio families, 727 MS cases and 604 healthy controls for 17 polymorphisms in MMP9, plasminogen activator urokinase (PLAU), PLAU receptor (PLAUR) and serpin peptidase inhibitor/clade 2/member B2 (SERPINB2) genes. No associations were found between the 17 polymorphisms and MS. Also, gene expression levels were analysed according to genotype: no associations were observed. In conclusion despite the consistent evidence for the role of MMP9 and the plasminogen activation cascade in MS, we found no associations between genotype nor gene expression. This suggested there are other potentially modifiable factors influencing gene expression in MS. © The Author(s) 2013.
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Nova |
2014 |
Smith CJA, Bensing S, Maltby VE, Zhang M, Scott RJ, Smith R, et al., 'Intermediate lobe immunoreactivity in a patient with suspected lymphocytic hypophysitis', Pituitary, 17 22-29 (2014) [C1]
Lymphocytic hypophysitis is an organ-specific autoimmune disease characterised by destruction of pituitary hormone-secreting cells due to attack by self-reactive T lymphocytes. Th... [more]
Lymphocytic hypophysitis is an organ-specific autoimmune disease characterised by destruction of pituitary hormone-secreting cells due to attack by self-reactive T lymphocytes. The spectrum of pituitary autoantibodies characterised by indirect immunofluorescence (IF) in these patients has not been substantially defined. The purpose of this study was to determine the spectrum of pituitary autoantibodies in 16 lymphocytic hypophysitis patients. Pituitary sections were prepared from guinea pigs and sera from 16 lymphocytic hypophysitis patients (13 biopsy proven and 3 suspected cases) and 13 healthy controls were evaluated for immunoreactivity to the pituitary tissue by immunofluorescence. A single patient was found to have high titre pituitary autoantibodies against guinea pig pituitary tissue. Immunoreactivity was directed against cells of the intermediate lobe. We present the case report of the patient who is a 24 year old woman that presented with headaches, polyuria and polydipsia. A uniformly enlarged pituitary mass was visible on MRI and a diagnosis of suspected lymphocytic hypophysitis was made. Based on our IF study, we postulate this patient has an autoimmune process directed towards the major cell type in the intermediate lobe, the melanotroph. Pre-adsorption with peptides representing adrenocorticotropic hormone, a-melanocyte stimulating hormone or ß-endorphin did not affect the IF signal suggesting our patient's pituitary autoantibodies may target some other product of Proopiomelanocortin (POMC) processing, such as corticotrophin-like intermediate peptide or ¿-lipoprotein. Alternatively, the autoantibodies may target a peptide completely unrelated to POMC processing. © 2013 Springer Science+Business Media New York.
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2014 |
Oldmeadow C, Holliday EG, McEvoy M, Scott R, Kwok JBJ, Mather K, et al., 'Concordance between direct and imputed APOE genotypes using 1000 genomes data', Journal of Alzheimer's Disease, 42 391-393 (2014) [C1]
There are a growing number of large cohorts of older persons with genome-wide genotyping data available, but APOE is not included in any of the common microarray platforms. We com... [more]
There are a growing number of large cohorts of older persons with genome-wide genotyping data available, but APOE is not included in any of the common microarray platforms. We compared directly measured APOE genotypes with those imputed using microarray data and the '1000 Genomes' dataset in a sample of 320 Caucasians. We find 90% agreement for e2/e3/e4 genotypes and 93% agreement for predicting e4 status, yielding kappa values of 0.81 and 0.84, respectively. More stringent thresholds around allele number estimates can increase this agreement to 90-97% and kappas of 0.90-0.93.
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2014 |
Spurdle AB, Couch FJ, Parsons MT, McGuffog L, Barrowdale D, Bolla MK, et al., 'Refined histopathological predictors of BRCA1 and BRCA2 mutation status: A large-scale analysis of breast cancer characteristics from the BCAC, CIMBA, and ENIGMA consortia', Breast Cancer Research, 16 3419 (2014) [C1]
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Nova |
2014 |
de Zeeuw EL, van Beijsterveldt CEM, Glasner TJ, Bartels M, Ehli EA, Davies GE, et al., 'Polygenic scores associated with educational attainment in adults predict educational achievement and ADHD symptoms in children', American Journal of Medical Genetics, Part B: Neuropsychiatric Genetics, 165 510-520 (2014) [C1]
The American Psychiatric Association estimates that 3 to 7 per cent of all school aged children are diagnosed with attention deficit hyperactivity disorder (ADHD). Even after corr... [more]
The American Psychiatric Association estimates that 3 to 7 per cent of all school aged children are diagnosed with attention deficit hyperactivity disorder (ADHD). Even after correcting for general cognitive ability, numerous studies report a negative association between ADHD and educational achievement. With polygenic scores we examined whether genetic variants that have a positive influence on educational attainment have a protective effect against ADHD. The effect sizes from a large GWA meta-analysis of educational attainment in adults were used to calculate polygenic scores in an independent sample of 12-year-old children from the Netherlands Twin Register. Linear mixed models showed that the polygenic scores significantly predicted educational achievement, school performance, ADHD symptoms and attention problems in children. These results confirm the genetic overlap between ADHD and educational achievement, indicating that one way to gain insight into genetic variants responsible for variation in ADHD is to include data on educational achievement, which are available at a larger scale. © 2014 Wiley Periodicals, Inc.
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2014 |
Greenop KR, Peters S, Bailey HD, Fritschi L, Attia J, Scott RJ, et al., 'Erratum to: Exposure to pesticides and the risk of childhood brain tumors', Cancer Causes and Control, 25 1239-1240 (2014)
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2014 |
Abdullah N, Attia J, Oldmeadow C, Scott RJ, Holliday EG, 'The Architecture of Risk for Type 2 Diabetes: Understanding Asia in the Context of Global Findings', INTERNATIONAL JOURNAL OF ENDOCRINOLOGY, 2014 (2014) [C1]
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Nova |
2014 |
Zyluk A, Paszkowska-Szczur K, Gupta S, Scott RJ, Lubinski J, Debniak T, 'Dupuytren's disease and the risk of malignant neoplasms', Hereditary Cancer in Clinical Practice, 12 (2014) [C1]
The object of this study was the investigation of the risk of occurrence of malignant neoplasms in 508 patients with Dupuytren's disease (DD) and in 2157 of their 1st degree ... [more]
The object of this study was the investigation of the risk of occurrence of malignant neoplasms in 508 patients with Dupuytren's disease (DD) and in 2157 of their 1st degree relatives. In the first stage of the study, we evaluated the tumour spectrum as well as the age of the patient at diagnosis of cancers in DD families along with the observed and expected frequencies of malignancies. In the second stage of the study, we examined the distribution of 20 common mutations/polymorphisms in 12 known cancer susceptibility genes among DD patients and 508 matched healthy controls. No such study has been published to date. Results. No significant differences were noted between malignancies diagnosed among members of DD families and the general population. Molecular examination of 20 mutations/polymorphisms in 12 cancer susceptibility genes in Dupuytren's patients and controls showed a statistically significant association of one mutation with Dupuytren disease: D312M in XPD (OR = 1.75, p = 0.004). We observed a tendency toward changed frequencies of occurrence of central nervous system tumors, laryngeal cancer and non-melanoma skin cancers in DD families. The results of our study indicate a lack of a strong association between Dupuytren disease and familial cancer risk. © 2014 Zyluk et al.; licensee BioMed Central Ltd.
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Nova |
2014 |
Masson AL, Talseth-Palmer BA, Evans TJ, Grice DM, Hannan GN, Scott RJ, 'Expanding the genetic basis of copy number variation in familial breast cancer', Hereditary Cancer in Clinical Practice, 12 (2014) [C1]
Introduction: Familial breast cancer (fBC) is generally associated with an early age of diagnosis and a higher frequency of disease among family members. Over the past two decades... [more]
Introduction: Familial breast cancer (fBC) is generally associated with an early age of diagnosis and a higher frequency of disease among family members. Over the past two decades a number of genes have been identified that are unequivocally associated with breast cancer (BC) risk but there remain a significant proportion of families that cannot be accounted for by these genes. Copy number variants (CNVs) are a form of genetic variation yet to be fully explored for their contribution to fBC. CNVs exert their effects by either being associated with whole or partial gene deletions or duplications and by interrupting epigenetic patterning thereby contributing to disease development. CNV analysis can also be used to identify new genes and loci which may be associated with disease risk.Methods: The Affymetrix Cytogenetic Whole Genome 2.7 M (Cyto2.7 M) arrays were used to detect regions of genomic re-arrangement in a cohort of 129 fBC BRCA1/BRCA2 mutation negative patients with a young age of diagnosis (<50 years) compared to 40 unaffected healthy controls (>55 years of age).Results: CNV analysis revealed the presence of 275 unique rearrangements that were not present in the control population suggestive of their involvement in BC risk. Several CNVs were found that have been previously reported as BC susceptibility genes. This included CNVs in RPA3, NBN (NBS1), MRE11A and CYP19A1 in five unrelated fBC patients suggesting that these genes are involved in BC initiation and/or progression. Of special interest was the identification of WWOX and FHIT rearrangements in three unrelated fBC patients.Conclusions: This study has identified a number of CNVs that potentially contribute to BC initiation and/or progression. The identification of CNVs that are associated with known tumour suppressor genes is of special interest that warrants further larger studies to understand their precise role in fBC. © 2014 Masson et al.; licensee BioMed Central Ltd.
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Scott RJ, Fox SB, Desai J, Grieu F, Amanuel B, Garrett K, et al., 'KRAS mutation testing of metastatic colorectal cancer in Australia: Where are we at?', Asia-Pacific Journal of Clinical Oncology, 10 261-265 (2014) [C1]
Aim: To carry out a nationwide study of KRAS testing in metastatic colorectal cancer as reported by nine major molecular pathology service providers in Australia, including mutati... [more]
Aim: To carry out a nationwide study of KRAS testing in metastatic colorectal cancer as reported by nine major molecular pathology service providers in Australia, including mutation frequencies and turnaround times that might impact on patient care. Methods: Participating laboratories contributed information on KRAS mutation frequencies, including the G13D mutation type, as well as turnaround times for tumor block retrieval and testing. Results: The KRAS mutation frequency observed by nine different test sites for a total of 3688 metastatic colorectal cancers ranged from 34.4% to 40.7%, with an average across all sites of 38.8%. The average frequency of the G13D mutation type among all cases was 8.0%. The median turnaround time was 17 days (range 0-191), with 20% of cases requiring more than 4 weeks for a KRAS test result. The major contributor to long turnaround times was the time taken to retrieve archived blocks of primary tumor, particularly from sources external to the test site. Conclusion: The frequency of KRAS mutations in metastatic colorectal cancer reported by the major Australian test sites is very similar to that reported by other large overseas studies. More widespread introduction of routine testing at the time of initial diagnosis should eliminate the long turnaround times currently being experienced in a significant proportion of cases. Future expansion of testing to include other KRAS and NRAS mutation hotspots may spur the introduction of next-generation sequencing platforms. © 2014 Wiley Publishing Asia Pty Ltd.
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Moscovis SM, Hall ST, Burns CJ, Scott RJ, Blackwell CC, 'The male excess in sudden infant deaths', INNATE IMMUNITY, 20 24-29 (2014) [C1]
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2014 |
Baines KJ, Simpson JL, Wood LG, Scott RJ, Fibbens NL, Powell H, et al., 'Sputum gene expression signature of 6 biomarkers discriminates asthma inflammatory phenotypes', Journal of Allergy and Clinical Immunology, 133 997-1007 (2014) [C1]
Background Airway inflammation is associated with asthma exacerbation risk, treatment response, and disease mechanisms. Objective This study aimed to identify and validate a sputu... [more]
Background Airway inflammation is associated with asthma exacerbation risk, treatment response, and disease mechanisms. Objective This study aimed to identify and validate a sputum gene expression signature that discriminates asthma inflammatory phenotypes. Methods An asthma phenotype biomarker discovery study generated gene expression profiles from induced sputum of 47 asthmatic patients. A clinical validation study (n = 59 asthmatic patients) confirmed differential expression of key genes. A 6-gene signature was identified and evaluated for reproducibility (n = 30 asthmatic patients and n = 20 control subjects) and prediction of inhaled corticosteroid (ICS) response (n = 71 asthmatic patients). Receiver operating characteristic curves were calculated, and area under the curve (AUC) values were reported. Results From 277 differentially expressed genes between asthma inflammatory phenotypes, we identified 23 genes that showed highly significant differential expression in both the discovery and validation populations. A signature of 6 genes, including Charcot-Leydon crystal protein (CLC); carboxypeptidase A3 (CPA3); deoxyribonuclease I-like 3 (DNASE1L3); IL-1ß (IL1B); alkaline phosphatase, tissue-nonspecific isozyme (ALPL); and chemokine (C-X-C motif) receptor 2 (CXCR2), was reproducible and could significantly (P <.0001) discriminate eosinophilic asthma from other phenotypes, including patients with noneosinophilic asthma (AUC, 89.6%), paucigranulocytic asthma (AUC, 92.6%), or neutrophilic asthma (AUC, 91.4%) and healthy control subjects (AUC, 97.6%), as well as discriminating patients with neutrophilic asthma from those with paucigranulocytic asthma (AUC, 85.7%) and healthy control subjects (AUC, 90.8). The 6-gene signature predicted ICS response (>12% change in FEV1; AUC, 91.5%). ICS treatment reduced the expression of CLC, CPA3, and DNASE1L3 in patients with eosinophilic asthma. Conclusions A sputum gene expression signature of 6 biomarkers reproducibly and significantly discriminates inflammatory phenotypes of asthma and predicts ICS treatment response. This signature has the potential to become a useful diagnostic tool to assist in the clinical diagnosis and management of asthma. © 2013 American Academy of Allergy, Asthma & Immunology.
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Gromowski T, Masojc B, Cybulski C, Górski B, Kluzniak W, Paszkowska-Szczur K, et al., 'Prevalence of the E318K and V320I MITF germline mutations in Polish cancer patients and multiorgan cancer risk-a population-based study', Cancer Genetics, (2014) [C1]
The E318K mutation in the MITF gene has been associated with a high risk of melanoma, renal cell carcinoma, and pancreatic cancer; the risk of other cancers has not been evaluated... [more]
The E318K mutation in the MITF gene has been associated with a high risk of melanoma, renal cell carcinoma, and pancreatic cancer; the risk of other cancers has not been evaluated so far. Herein, we examined the possible association of E318K and a novel variant of the MITF gene, V320I, with the risk of cancers of different sites of origin in a Polish population. We assayed for the presence of the E318K and V320I missense mutations in 4,226 patients with one of six various cancers (melanoma or cancer of the kidney, lung, prostate, colon, or breast) and 2,114 controls from Poland. The E318K mutation was detected in 4 of 2,114 participants (0.19%) in the Polish control population, the V320I in 3 of 2,114 participants (0.14%) in the control group. We found no statistically significant differences in the prevalence of the E318K and V320I variants among cases and controls. We found two carriers of the E318K variant among melanoma patients (P = 0.95), one carrier among breast cancer patients (P = 0.77), one carrier among colorectal cancer patients (P = 0.82), and one carrier among kidney cancer patients (P = 0.64). Our study demonstrates a lack of strong association of E318K and V320I with increased risk of melanoma or cancers of the kidney, breast, prostate, lung, or colon. © 2014 Elsevier Inc. All rights reserved.
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Shahijanian F, Parnell GP, McKay FC, Gatt PN, Shojoei M, O'Connor KS, et al., 'The CYP27B1 variant associated with an increased risk of autoimmune disease is underexpressed in tolerizing dendritic cells', HUMAN MOLECULAR GENETICS, 23 1425-1434 (2014) [C1]
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Goris A, van Setten J, Diekstra F, Ripke S, Patsopoulos NA, Sawcer SJ, et al., 'No evidence for shared genetic basis of common variants in multiple sclerosis and amyotrophic lateral sclerosis', HUMAN MOLECULAR GENETICS, 23 1916-1922 (2014) [C1]
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Rudnicka H, Masojc B, van de Wetering T, Debniak T, Cybulski C, Gronwald J, et al., 'First recurrent large genomic rearrangement in the BRCA1 gene found in Poland', Cancer Epidemiology, (2014) [C1]
Mutation in the BRCA1 gene increases the risk of the person developing breast and/or ovarian cancer. The prevalence and spectrum of large genomic rearrangements (LGRs) varies cons... [more]
Mutation in the BRCA1 gene increases the risk of the person developing breast and/or ovarian cancer. The prevalence and spectrum of large genomic rearrangements (LGRs) varies considerably among different tested populations. In our previous study we described three LGRs in BRCA1 (exons 13-19, exon 17 and exon 22) in Polish families at high risk of breast and ovarian cancer. In this study we analyzed a group of 550 unselected women with ovarian cancer for the three previously identified LGRs. We used a rapid, single-step and closed-tube method: high-resolution melting analysis (HRMA). In this group of unrelated patients diagnosed with ovarian cancer we found three cases with the same deletions of exon 22. This is the first recurrent large deletion in BRCA1 found in Poland. We conclude that screening for the exon 22 deletion in BRCA1 should be included in the Polish BRCA1 genetic testing panel and possibly extended into other Slavic populations. © 2014 Elsevier Ltd. All rights reserved.
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Avery-Kiejda KA, Braye SG, Mathe A, Forbes JF, Scott RJ, 'Decreased expression of key tumour suppressor microRNAs is associated with lymph node metastases in triple negative breast cancer', BMC Cancer, 14 (2014) [C1]
Background: Breast cancer is the most common malignancy that develops in women, responsible for the highest cancer-associated death rates. Triple negative breast cancers represent... [more]
Background: Breast cancer is the most common malignancy that develops in women, responsible for the highest cancer-associated death rates. Triple negative breast cancers represent an important subtype that have an aggressive clinical phenotype, are associated with a higher likelihood of metastasis and are not responsive to current targeted therapies. miRNAs have emerged as an attractive candidate for molecular biomarkers and treatment targets in breast cancer, but their role in the progression of triple negative breast cancer remains largely unexplored.Methods: This study has investigated miRNA expression profiles in 31 primary triple negative breast cancer cases and in 13 matched lymph node metastases compared with 23 matched normal breast tissues to determine miRNAs associated with the initiation of this disease subtype and those associated with its metastasis.Results: 71 miRNAs were differentially expressed in triple negative breast cancer, the majority of which have previously been associated with breast cancer, including members of the miR-200 family and the miR-17-92 oncogenic cluster, suggesting that the majority of miRNAs involved in the initiation of triple negative breast cancer are not subtype specific. However, the repertoire of miRNAs expressed in lymph node negative and lymph node positive triple negative breast cancers were largely distinct from one another. In particular, miRNA profiles associated with lymph node negative disease tended to be up-regulated, while those associated with lymph node positive disease were down-regulated and largely overlapped with the profiles of their matched lymph node metastases. From this, 27 miRNAs were identified that are associated with metastatic capability in the triple negative breast cancer subtype.Conclusions: These results provide novel insight into the repertoire of miRNAs that contribute to the initiation of and progression to lymph node metastasis in triple negative breast cancer and have important implications for the treatment of this breast cancer subtype. © 2014 Avery-Kiejda et al.; licensee BioMed Central Ltd.
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Moscovis S, Hall S, Burns C, Scott R, Blackwell C, 'Development of an experimental model for assessing the effects of cigarette smoke and virus infections on inflammatory responses to bacterial antigens', Innate Immunity, 20 647-658 (2014) [C1]
Interactions among major risk factors associated with bacterial infections were assessed in a model system using surrogates for virus infection; IFN-g, and exposure to cigarette s... [more]
Interactions among major risk factors associated with bacterial infections were assessed in a model system using surrogates for virus infection; IFN-g, and exposure to cigarette smoke; cigarette smoke extract (CSE), nicotine and cotinine. Cytokine responses elicited by LPS from THP-1 cells in the presence of these components, or combinations of components, were assessed by multiplex bead assay, i.e. IL-1ß, IL-6, IL-8, IL-10, TNF-a and IFN-¿. IFN-¿-priming significantly increased pro-inflammatory cytokines induced by LPS. CSE suppressed production of pro-inflammatory cytokines IL-1ß, TNF-a and IFN-¿, but enhanced production of IL-8. Nicotine and cotinine suppressed all cytokine responses. In combination, IFN-¿ masked the inhibitory effects of CSE. In relation to the objectives of the study, we concluded that (a) IFN¿ at biologically relevant concentrations significantly enhanced pro-inflammatory responses; (b) CSE, nicotine and cotinine dysregulated the inflammatory response and that the effects of CSE were different from those of the individual components, nicotine and cotinine; (c) when both IFN-¿ and CSE were present, IFN-¿ masked the effect of CSE. There is a need for clinical investigations on the increase in IL-8 responses in relation to exposure to cigarette smoke and increased pro-inflammatory responses in relation to recent viral infection. © 2013 The Author(s).
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Avery-Kiejda KA, Morten B, Wong-Brown MW, Mathe A, Scott RJ, 'The relative mRNA expression of p53 isoforms in breast cancer is associated with clinical features and outcome.', Carcinogenesis, 35 586-596 (2014) [C1]
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2014 |
Cox AJ, Moscovis SM, Blackwell CC, Scott RJ, 'Cytokine gene polymorphism among Indigenous Australians.', Innate Immun, 20 431-439 (2014) [C1]
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2013 |
Masson AL, Talseth-Palmer BA, Evans T-J, Grice DM, Duesing K, Hannan GN, Scott RJ, 'Copy number variation in hereditary non-polyposis colorectal cancer', Genes, 4 536-555 (2013) [C1]
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2013 |
Mechelli R, Umeton R, Policano C, Annibali V, Coarelli G, Ricigliano VAG, et al., 'A "Candidate-Interactome" Aggregate Analysis of Genome-Wide Association Data in Multiple Sclerosis', PLoS ONE, 8 (2013) [C1]
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2013 |
Terwisscha van Scheltinga AF, Bakker SC, van Haren NEM, Derks EM, Buizer-Voskamp JE, Boos HBM, et al., 'Genetic Schizophrenia Risk Variants Jointly Modulate Total Brain and White Matter Volume', Biological Psychiatry, 73 525-531 (2013) [C1]
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2013 |
Wong-Brown MW, McPhillips ML, Hipwell M, Pecenpetelovska G, Dooley S, Meldrum C, Scott RJ, 'cDNA analysis of the BRCA1 unclassified variant c.5194-12G \ A', CLINICAL GENETICS, 84 505-506 (2013) [C3]
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2013 |
Talseth-Palmer BA, Wijnen JT, Barker D, Vasen HFA, Scott RJ, 'Is the reported modifying effect of 8q23.3 and 11q23.1 on colorectal cancer risk for MLH1 mutation carriers valid? Reply', INTERNATIONAL JOURNAL OF CANCER, 133 1764-1764 (2013) [C3]
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Talseth-Palmer B, Wijnen JT, Brenne IS, Jagmohan-Changur S, Barker DJ, Ashton KA, et al., 'Combined analysis of three Lynch syndrome cohorts confirms the modifying effects of 8q23.3 and 11q23.1 in MLH1 mutation carriers', International Journal of Cancer, 132 1487-1729 (2013) [C1]
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Titmarsh CJ, Moscovis SM, Hall S, Tzanakaki G, Kesanopoulos K, Xirogianni A, et al., 'Comparison of cytokine gene polymorphisms among Greek patients with invasive meningococcal disease or viral meningitis', JOURNAL OF MEDICAL MICROBIOLOGY, 62 694-700 (2013) [C1]
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2013 |
Gardiner EJ, Cairns MJ, Liu B, Beveridge NJ, Carr V, Kelly B, et al., 'Gene expression analysis reveals schizophrenia-associated dysregulation of immune pathways in peripheral blood mononuclear cells', JOURNAL OF PSYCHIATRIC RESEARCH, 47 425-437 (2013) [C1]
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Van Scheltinga AFT, Bakker SC, Van Haren NEM, Derks EM, Buizer-Voskamp JE, Cahn W, et al., 'Schizophrenia genetic variants are not associated with intelligence', Psychological Medicine, 43 2563-2570 (2013) [C1]
Background Schizophrenia is associated with lower pre-morbid intelligence (IQ) in addition to (pre-morbid) cognitive decline. Both schizophrenia and IQ are highly heritable traits... [more]
Background Schizophrenia is associated with lower pre-morbid intelligence (IQ) in addition to (pre-morbid) cognitive decline. Both schizophrenia and IQ are highly heritable traits. Therefore, we hypothesized that genetic variants associated with schizophrenia, including copy number variants (CNVs) and a polygenic schizophrenia (risk) score (PSS), may influence intelligence. Method IQ was estimated with the Wechsler Adult Intelligence Scale (WAIS). CNVs were determined from single nucleotide polymorphism (SNP) data using the QuantiSNP and PennCNV algorithms. For the PSS, odds ratios for genome-wide SNP data were calculated in a sample collected by the Psychiatric Genome-Wide Association Study (GWAS) Consortium (8690 schizophrenia patients and 11 831 controls). These were used to calculate individual PSSs in our independent sample of 350 schizophrenia patients and 322 healthy controls. Results Although significantly more genes were disrupted by deletions in schizophrenia patients compared to controls (p = 0.009), there was no effect of CNV measures on IQ. The PSS was associated with disease status (R 2 = 0.055, p = 2.1 × 10 -7) and with IQ in the entire sample (R 2 = 0.018, p = 0.0008) but the effect on IQ disappeared after correction for disease status. Conclusions Our data suggest that rare and common schizophrenia-associated variants do not explain the variation in IQ in healthy subjects or in schizophrenia patients. Thus, reductions in IQ in schizophrenia patients may be secondary to other processes related to schizophrenia risk. © Cambridge University Press 2013.
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Yadav S, Cotlarciuc I, Munroe PB, Khan MS, Nalls MA, Bevan S, et al., 'Genome-Wide Analysis of Blood Pressure Variability and Ischemic Stroke', Stroke, 44 2703-2709 (2013) [C1]
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Köttgen A, Albrecht E, Teumer A, Vitart V, Krumsiek J, Hundertmark C, et al., 'Genome-wide association analyses identify 18 new loci associated with serum urate concentrations', Nature Genetics, 45 145-154 (2013) [C1]
Elevated serum urate concentrations can cause gout, a prevalent and painful inflammatory arthritis. By combining data from >140,000 individuals of European ancestry within the ... [more]
Elevated serum urate concentrations can cause gout, a prevalent and painful inflammatory arthritis. By combining data from >140,000 individuals of European ancestry within the Global Urate Genetics Consortium (GUGC), we identified and replicated 28 genome-wide significant loci in association with serum urate concentrations (18 new regions in or near TRIM46, INHBB, SFMBT1, TMEM171, VEGFA, BAZ1B, PRKAG2, STC1, HNF4G, A1CF, ATXN2, UBE2Q2, IGF1R, NFAT5, MAF, HLF, ACVR1B-ACVRL1 and B3GNT4). Associations for many of the loci were of similar magnitude in individuals of non-European ancestry. We further characterized these loci for associations with gout, transcript expression and the fractional excretion of urate. Network analyses implicate the inhibins-activins signaling pathways and glucose metabolism in systemic urate control. New candidate genes for serum urate concentration highlight the importance of metabolic control of urate production and excretion, which may have implications for the treatment and prevention of gout. © 2013 Nature America, Inc. All rights reserved.
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Chen J, Pande M, Huang Y-J, Wei C, Amos CI, Talseth-Palmer BA, et al., 'Cell cycle-related genes as modifiers of age of onset of colorectal cancer in Lynch syndrome: a large-scale study in non-Hispanic white patients', CARCINOGENESIS, 34 299-306 (2013) [C1]
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Schache M, Richardson AJ, Mitchell P, Wang JJ, Rochtchina E, Viswanathan AC, et al., 'Genetic association of refractive error and axial length with 15q14 but not 15q25 in the Blue Mountains Eye Study Cohort', Ophthalmology, 120 292-297 (2013) [C1]
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Barzideh J, Scott RJ, Aitken RJ, 'Analysis of the global methylation status of human spermatozoa and its association with the tendency of these cells to enter apoptosis', ANDROLOGIA, 45 424-429 (2013) [C1]
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2013 |
Acikyol B, Graham RM, Trinder D, House MJ, Olynyk JK, Scott RJ, et al., 'Brain transcriptome perturbations in the transferrin receptor 2 mutant mouse support the case for brain changes in iron loading disorders, including effects relating to long-term depression and long-term potentiation', Neuroscience, 235 119-128 (2013) [C1]
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Williams FMK, Carter AM, Hysi PG, Surdulescu G, Hodgkiss D, Soranzo N, et al., 'Ischemic stroke is associated with the ABO locus: The EuroCLOT Study', Annals of Neurology, 73 16-31 (2013) [C1]
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Greenop KR, Peters S, Bailey HD, Fritschi L, Attia J, Scott RJ, et al., 'Exposure to pesticides and the risk of childhood brain tumors', CANCER CAUSES & CONTROL, 24 1269-1278 (2013) [C1]
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Milne E, Greenop KR, Scott RJ, De Klerk NH, Bower C, Ashton LJ, et al., 'Parental alcohol consumption and risk of childhood acute lymphoblastic leukemia and brain tumors', Cancer Causes and Control, 24 391-402 (2013) [C1]
Purpose: Childhood acute lymphoblastic leukemia (ALL) is the most common childhood malignancy and brain tumors (CBTs) are the leading cause of cancer death in children. In our Aus... [more]
Purpose: Childhood acute lymphoblastic leukemia (ALL) is the most common childhood malignancy and brain tumors (CBTs) are the leading cause of cancer death in children. In our Australian case-control studies of these cancers, we investigated whether parental alcohol consumption before or during pregnancy was associated with risk. Methods: Cases were identified through the ten Australian pediatric oncology centers, and controls were recruited through national random-digit dialling. Detailed information on alcohol consumption, including beverage type, amount, and timing, was collected from 690 case families (388 ALL and 302 CBT) and 1,396 control families. Data were analyzed using unconditional logistic regression. Results: We found no evidence that maternal alcohol use before or during pregnancy was associated with an increased risk of either cancer; rather, there was evidence of inverse associations, particularly with wine. For both cancers, we observed U-shaped associations with paternal alcohol consumption in the year before the pregnancy, possibly driven by reduced risk at moderate levels of beer and wine intake and increased risk associated with high levels of beer intake. Moderate intake of spirits by fathers was associated with an increased risk of CBT but not ALL. These findings would be strengthened by corroboration in other studies. While the inverse associations with wine may be interesting mechanistically, the public health message remains that maternal alcohol use during pregnancy causes serious disorders in the offspring and should be avoided. Conclusions: Our findings suggest that men, as well as women, should limit their alcohol intake when planning a pregnancy. © 2012 Springer Science+Business Media Dordrecht.
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Lee SH, Harold D, Nyholt DR, Goddard ME, Zondervan KT, Williams J, et al., 'Estimation and partitioning of polygenic variation captured by common SNPs for Alzheimer's disease, multiple sclerosis and endometriosis', HUMAN MOLECULAR GENETICS, 22 832-841 (2013) [C1]
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Cortes A, Field J, Glazov EA, Hadler J, Stankovich J, Brown MA, 'Resequencing and fine-mapping of the chromosome 12q13-14 locus associated with multiple sclerosis refines the number of implicated genes', HUMAN MOLECULAR GENETICS, 22 2283-2292 (2013) [C1]
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Rietveld CA, Medland SE, Derringer J, Yang J, Esko T, Martin NW, et al., 'GWAS of 126,559 individuals identifies genetic variants associated with educational attainment', Science, 340 1467-1471 (2013) [C1]
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Paszkowska-Szczur K, Scott RJ, Serrano-Fernandez P, Mirecka A, Gapska P, Górski B, et al., 'Xeroderma pigmentosum genes and melanoma risk', International Journal of Cancer, 133 1094-1101 (2013) [C1]
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Milne E, Greenop KR, Scott RJ, Ashton LJ, Cohn RJ, de Klerk NH, Armstrong BK, 'Parental smoking and risk of childhood brain tumors', International Journal of Cancer, 133 253-259 (2013) [C1]
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Cox MB, Bowden NA, Scott RJ, Lechner-Scott J, 'Altered expression of the plasminogen activation pathway in peripheral blood mononuclear cells in multiple sclerosis: possible pathomechanism of matrix metalloproteinase activation', Multiple Sclerosis Journal, 19 1268-1274 (2013) [C1]
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Green MJ, Cairns MJ, Wu J, Dragovic M, Jablensky A, Tooney PA, et al., 'Genome-wide supported variant
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Green MJ, Cairns MJ, Wu J, Dragovic M, Jablensky A, Tooney PA, et al., 'Genome-wide supported variant MIR137 and severe negative symptoms predict membership of an impaired cognitive subtype of schizophrenia', Molecular Psychiatry, (2013)
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Talseth-Palmer BA, Wijnen JT, Grice DM, Scott RJ, 'Genetic modifiers of cancer risk in Lynch syndrome: a review', FAMILIAL CANCER, 12 207-216 (2013) [C1]
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Stambolian D, Wojciechowski R, Oexle K, Pirastu M, Li X, Raffel LJ, et al., 'Meta-analysis of genome-wide association studies in five cohorts reveals common variants in RBFOX1, a regulator of tissue-specific splicing, associated with refractive error', Human Molecular Genetics, 22 2754-2764 (2013) [C1]
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Kumarasinghe N, Beveridge NJ, Gardiner E, Scott RJ, Yasawardene S, Perera A, et al., 'Gene expression profiling in treatment-naive schizophrenia patients identifies abnormalities in biological pathways involving
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Bolton KA, Ross JP, Grice DM, Bowden NA, Holliday EG, Avery-Kiejda KA, Scott RJ, 'STaRRRT: a table of short tandem repeats in regulatory regions of the human genome', BMC GENOMICS, 14 (2013) [C1]
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Lener MR, Gupta S, Scott RJ, Tootsi M, Kulp M, Tammesoo M, et al., 'Can selenium levels act as a marker of colorectal cancer risk?', BMC Cancer, 13 xx-xx (2013) [C1]
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Patsopoulos NA, Barcellos LF, Hintzen RQ, Schaefer C, Van Duijn CM, Noble JA, et al., 'Fine-Mapping the Genetic Association of the Major Histocompatibility Complex in Multiple Sclerosis: HLA and Non-HLA Effects', PLOS GENETICS, 9 (2013) [C1]
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Schork AJ, Thompson WK, Pham P, Torkamani A, Roddey JC, Sullivan PF, et al., 'All SNPs Are Not Created Equal: Genome-Wide Association Studies Reveal a Consistent Pattern of Enrichment among Functionally Annotated SNPs', PLOS GENETICS, 9 (2013) [C1]
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Talseth-Palmer BA, Wijnen JT, Andreassen EK, Barker D, Jagmohan-Changur S, Tops CM, et al., 'The importance of a large sample cohort for studies on modifier genes influencing disease severity in FAP patients.', Hered Cancer Clin Pract, 11 20 (2013) [C1]
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Talseth-Palmer B, Holliday EG, Evans T-J, McEvoy MA, Attia JR, Grice DM, et al., 'Continuing difficulties in interpreting CNV data: Lessons from a genome-wide CNV association study of Australian HNPCC/lynch syndrome patients', BMC Medical Genomics, 6 1-13 (2013) [C1]
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Lin R, Charlesworth J, Stankovich J, Perreau VM, Brown MA, Taylor BV, Moscato P, 'Identity-by-Descent Mapping to Detect Rare Variants Conferring Susceptibility to Multiple Sclerosis', PLOS ONE, 8 (2013) [C1]
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Bowden NA, Ashton KA, Vilain RE, Avery-Kiejda KA, Davey RJ, Murray HC, et al., 'Regulators of Global Genome Repair Do Not Respond to DNA Damaging Therapy but Correlate with Survival in Melanoma', PLOS ONE, 8 (2013) [C1]
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Picelli S, Lorenzo Bermejo J, Chang-Claude J, Hoffmeister M, Fernandez-Rozadilla C, Carracedo A, et al., 'Meta-Analysis of Mismatch Repair Polymorphisms within the Cogent Consortium for Colorectal Cancer Susceptibility', PLOS ONE, 8 (2013) [C1]
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Sun C, Young TL, Mackey DA, Van Zuydam NR, Doney ASF, Palmer CNA, et al., 'Genetic loci for retinal arteriolar microcirculation', PLoS One, 8 (2013) [C1]
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Jensen RA, Sim X, Li X, Cotch MF, Ikram MK, Holliday EG, et al., 'Genome-wide association study of retinopathy in individuals without diabetes', PLoS One, 8 (2013) [C1]
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Holliday EG, Smith AV, Cornes BK, Buitendijk GHS, Jensen RA, Sim X, et al., 'Insights into the genetic architecture of early stage age-related macular degeneration: A genome-wide association study meta-analysis', PLoS One, 8 (2013) [C1]
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2013 |
Johnstone DM, Riveros C, Heidari M, Graham RM, Trinder D, Berretta R, et al., 'Evaluation of Different Normalization and Analysis Procedures for Illumina Gene Expression Microarray Data Involving Small Changes', Microarrays, 2 131-152 (2013) [C1]
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Nova |
2012 |
Houlston RS, 'COGENT (COlorectal cancer GENeTics) revisited', MUTAGENESIS, 27 143-151 (2012)
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2012 |
Milne E, Greenop KR, Scott R, Bailey HD, Attia JR, Dalla-Pozza L, et al., 'Parental prenatal smoking and risk of childhood acute lymphoblastic leukemia', American Journal of Epidemiology, 175 43-53 (2012) [C1]
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Nova |
2012 |
Johnstone DM, Graham RM, Trinder D, Delima RD, Riveros RC, Olynyk JK, et al., 'Brain transcriptome perturbations in the Hfe(-/-) mouse model of genetic iron loading', Brain Research, 1448 144-152 (2012) [C1]
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Nova |
2012 |
Van Der Luijt RB, Devilee P, Easton DF, Peock S, Frost D, Platte R, et al., 'Association of PHB 1630 C \ T and MTHFR 677 C \ T polymorphisms with breast and ovarian cancer risk in BRCA1/2 mutation carriers: results from a multicenter study', British Journal of Cancer, 106 2016-2024 (2012) [C1]
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Nova |
2012 |
Lill CM, Liu T, Schjeide B-MM, Roehr JT, Akkad DA, Damotte V, et al., 'Closing the case of APOE in multiple sclerosis: no association with disease risk in over 29 000 subjects', Journal of Medical Genetics, 49 558-562 (2012) [C1]
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Nova |
2012 |
Ashton KA, Scurry JP, Rutherford J, Otton GR, Scott R, Bowden NA, 'Nodular prurigo of the vulva', Pathology, 44 565-567 (2012) [C3]
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2012 |
Young KMN, Scurry JP, Jaaback KS, Bowden NA, Scott R, 'Bilateral dysgerminoma associated with gonadoblastoma and sex-cord stromal tumour with annular tubules in a 28-year-old fertile woman with normal karyotype', Pathology, 44 257-260 (2012) [C3]
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Nova |
2012 |
Cheng YC, Anderson CD, Bione S, Keene K, Maguire JM, Nalls M, et al., 'Are myocardial infarction-associated single-nucleotide polymorphisms associated with ischemic stroke?', Stroke, 43 980-U143 (2012) [C1]
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Nova |
2012 |
Bailey HD, Miller M, Langridge A, De Klerk NH, Van Bockxmeer FM, Attia JR, et al., 'Maternal dietary intake of folate and vitamins B6 and B12 during pregnancy and the risk of childhood acute lymphoblastic leukemia', Nutrition and Cancer, 64 1122-1130 (2012) [C1]
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Nova |
2012 |
Leu C, De Kovel CGF, Zara F, Striano P, Pezzella M, Robbiano A, et al., 'Genome-wide linkage meta-analysis identifies susceptibility loci at 2q34 and 13q31.3 for genetic generalized epilepsies', Epilepsia, 53 308-318 (2012)
Purpose: Genetic generalized epilepsies (GGEs) have a lifetime prevalence of 0.3% with heritability estimates of 80%. A considerable proportion of families with siblings affected ... [more]
Purpose: Genetic generalized epilepsies (GGEs) have a lifetime prevalence of 0.3% with heritability estimates of 80%. A considerable proportion of families with siblings affected by GGEs presumably display an oligogenic inheritance. The present genome-wide linkage meta-analysis aimed to map: (1) susceptibility loci shared by a broad spectrum of GGEs, and (2) seizure type-related genetic factors preferentially predisposing to either typical absence or myoclonic seizures, respectively. Methods: Meta-analysis of three genome-wide linkage datasets was carried out in 379 GGE-multiplex families of European ancestry including 982 relatives with GGEs. To dissect out seizure type-related susceptibility genes, two family subgroups were stratified comprising 235 families with predominantly genetic absence epilepsies (GAEs) and 118 families with an aggregation of juvenile myoclonic epilepsy (JME). To map shared and seizure type-related susceptibility loci, both nonparametric loci (NPL) and parametric linkage analyses were performed for a broad trait model (GGEs) in the entire set of GGE-multiplex families and a narrow trait model (typical absence or myoclonic seizures) in the subgroups of JME and GAE families. Key Findings: For the entire set of 379 GGE-multiplex families, linkage analysis revealed six loci achieving suggestive evidence for linkage at 1p36.22, 3p14.2, 5q34, 13q12.12, 13q31.3, and 19q13.42. The linkage finding at 5q34 was consistently supported by both NPL and parametric linkage results across all three family groups. A genome-wide significant nonparametric logarithm of odds score of 3.43 was obtained at 2q34 in 118 JME families. Significant parametric linkage to 13q31.3 was found in 235 GAE families assuming recessive inheritance (heterogeneity logarithm of odds = 5.02). Significance: Our linkage results support an oligogenic predisposition of familial GGE syndromes. The genetic risk factor at 5q34 confers risk to a broad spectrum of familial GGE syndromes, whereas susceptibility loci at 2q34 and 13q31.3 preferentially predispose to myoclonic seizures or absence seizures, respectively. Phenotype- genotype strategies applying narrow trait definitions in phenotypic homogeneous subgroups of families improve the prospects of disentangling the genetic basis of common familial GGE syndromes.
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2012 |
Smith CJ, Bensing S, Burns C, Robinson PJ, Kasperlik-Zaluska AA, Scott R, et al., 'Identification of TPIT and other novel autoantigens in lymphocytic hypophysitis; immunoscreening of a pituitary cDNA library and development of immunoprecipitation assays', European Journal of Endocrinology, 166 391-398 (2012) [C1]
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Nova |
2012 |
Orsi L, Rudant J, Bonaventure A, Goujon-Bellec S, Corda E, Evans T-J, et al., 'Genetic polymorphisms and childhood acute lymphoblastic leukemia: GWAS of the ESCALE study (SFCE)', Leukemia, 26 2561-2564 (2012) [C1]
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Nova |
2012 |
Talseth-Palmer B, Scott R, Vasen HFA, Wijnen JT, '8q23.3 and 11q23.1 as modifying loci influencing the risk for CRC in Lynch syndrome', European Journal of Human Genetics, 20 487-488 (2012) [C3]
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Nova |
2012 |
Milne E, Greenop KR, Bower C, Miller M, Van Bockxmeer FM, Scott R, et al., 'Maternal use of folic acid and other supplements and risk of childhood brain tumors', Cancer Epidemiology Biomarkers and Prevention, 21 1933-1941 (2012) [C1]
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Nova |
2012 |
Long J, Zheng W, Xiang Y-B, Lose F, Thompson D, Tomlinson I, et al., 'Genome-wide association study identifies a possible susceptibility locus for endometrial cancer', Cancer Epidemiology, Biomarkers & Prevention, 21 980-987 (2012) [C1]
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Nova |
2012 |
Nyholt DR, Low S-K, Anderson CA, Painter JN, Uno S, Morris AP, et al., 'Genome-wide association meta-analysis identifies new endometriosis risk loci', Nature Genetics, 44 1355-1359 (2012) [C1]
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Nova |
2012 |
Holliday EG, Maguire JM, Evans T-J, Koblar SA, Jannes J, Sturm J, et al., 'Common variants at 6p21.1 are associated with large artery atherosclerotic stroke', Nature Genetics, 44 1147-1153 (2012) [C1]
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Nova |
2012 |
Okada Y, Sim X, Go MJ, Wu J-Y, Gu D, Takeuchi F, et al., 'Meta-analysis identifies multiple loci associated with kidney function-related traits in east Asian populations', Nature Genetics, 44 904-909 (2012) [C1]
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Nova |
2012 |
Gardiner EJ, Beveridge NJ, Wu JQ, Carr VJ, Scott R, Tooney PA, Cairns MJ, 'Imprinted DLK1-DIO3 region of 14q32 defines a schizophrenia-associated miRNA signature in peripheral blood mononuclear cells', Molecular Psychiatry, 17 827-840 (2012) [C1]
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Nova |
2012 |
Johnstone DM, Graham RM, Trinder D, Riveros RC, Olynyk JK, Scott R, et al., 'Changes in brain transcripts related to Alzheimer's disease in a model of HFE hemochromatosis are not consistent with increased Alzheimer's disease risk', Journal of Alzheimers Disease, 30 791-803 (2012) [C1]
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Nova |
2012 |
Yan J, Liu J, Lin CY, Scott R, Lechner-Scott J, Brown MA, et al., 'Interleukin-6 gene promoter-572 C allele may play a role in rate of disease progression in multiple sclerosis', International Journal of Molecular Sciences, 13 13667-13679 (2012) [C1]
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Nova |
2012 |
Mathers JC, Movahedi M, Macrae F, Mecklin J-P, Moeslein G, Olschwang S, et al., 'Long-term effect of resistant starch on cancer risk in carriers of hereditary colorectal cancer: an analysis from the CAPP2 randomised controlled trial', LANCET ONCOLOGY, 13 1242-1249 (2012) [C1]
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2012 |
Cox MB, Ban M, Bowden NA, Baker A, Scott R, Lechner-Scott J, 'Potential association of vitamin D receptor polymorphism Taq1 with multiple sclerosis', Multiple Sclerosis Journal, 18 16-22 (2012) [C1]
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Nova |
2012 |
Reeves SG, Meldrum C, Groombridge C, Spigelman A, Suchy J, Kurzawski G, et al., 'DNA repair gene polymorphisms and risk of early onset colorectal cancer in Lynch syndrome', Cancer Epidemiology, 36 183-189 (2012) [C1]
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Nova |
2012 |
Kurzawski G, Dymerska D, Serrano-Fernandez P, Trubicka J, Masojc BO, Jakubowska A, Scott R, 'DNA and RNA analyses in detection of genetic predisposition to cancer', Hereditary Cancer in Clinical Practice, 10 17 (2012) [C1]
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Nova |
2012 |
Kim K-T, Carroll AP, Mashkani B, Cairns MJ, Small D, Scott R, 'MicroRNA-16 Is down-regulated in mutated FLT3 expressing murine myeloid FDC-P1 cells and interacts with Pim-1', PLOS One, 7 (2012) [C1]
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Nova |
2012 |
Wu JQ, Wang X, Beveridge NJ, Tooney PA, Scott R, Carr VJ, Cairns MJ, 'Transcriptome sequencing revealed significant alteration of cortical promoter usage and splicing in schizophrenia', PLoS One, 7 (2012) [C1]
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Nova |
2012 |
Kim K-T, Mossman D, Small D, Scott R, 'Gene expression profiling of human myeloid leukemic MV4-11 cells treated with 5-Aza-2-deoxycytidine', Journal of Cancer Therapy, 3 177-182 (2012) [C1] |
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Nova |
2011 |
Ritchie ME, Ruijie L, Carvalho BS, Irizarry RA, Bahlo M, Booth DR, et al., 'Comparing genotyping algorithms for Illumina's Infinium whole-genome SNP BeadChips', BMC Bioinformatics, 12 68-79 (2011) [C1]
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Nova |
2011 |
Kiejda KA, Bowden NA, Croft AJ, Scurr LL, Kairupan CF, Ashton KA, et al., 'P53 in human melanoma fails to regulate target genes associated with apoptosis and the cell cycle and may contribute to proliferation', BMC Cancer, 11 203-219 (2011) [C1]
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Nova |
2011 |
Hondow HL, Fox SB, Mitchell G, Scott R, Beshay V, Wong SQ, et al., 'A high-throughput protocol for mutation scanning of the BRCA1 and BRCA2 genes', BMC Cancer, 11 265 (2011) [C1]
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Nova |
2011 |
Patsopoulos NA, De Bakker PIW, Esposito F, Reischl J, Lehr S, Bauer D, et al., 'Genome-wide meta-analysis identifies novel multiple sclerosis susceptibility loci', Annals of Neurology, 70 897-912 (2011) [C1]
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Nova |
2011 |
Talseth-Palmer B, Scott R, 'Genetic variation and its role in malignancy', International Journal of Biomedical Science, 7 158-171 (2011) [C1]
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Nova |
2011 |
De Bakker PIW, Kappos L, Polman CH, Chibnik LB, Hafler DA, Matthews PM, et al., 'Modeling the cumulative genetic risk for multiple sclerosis from genome-wide association data', Genome Medicine, 3 1-11 (2011) [C1]
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Nova |
2011 |
Mossman D, Scott R, 'Long term transcriptional reactivation of epigenetically silenced genes in colorectal cancer cells requires DNA hypomethylation and histone acetylation', PLoS ONE, 6 (2011) [C1]
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Nova |
2011 |
Jaworowska E, Trubicka J, Lener MR, Masojc B, Zlowocka-Perlowska E, McKay JD, et al., 'Smoking related cancers and loci at chromosomes 15q25, 5p15, 6p22.1 and 6p21.33 in the Polish population', PLoS ONE, 6 (2011) [C1]
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Nova |
2011 |
Ma GZM, Stankovich J, Kilpatrick TJ, Binder MD, Field J, Bahlo M, et al., 'Polymorphisms in the receptor tyrosine kinase MERTK gene are associated with multiple sclerosis susceptibility', PLoS ONE, 6 1-6 (2011) [C1]
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Nova |
2011 |
Reid A, Glass DC, Bailey HD, Milne E, De Klerk NH, Downie P, et al., 'Risk of childhood acute lymphoblastic leukaemia following parental occupational exposure to extremely low frequency electromagnetic fields', British Journal of Cancer, 105 1409-1413 (2011) [C1]
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2011 |
Vilain RE, Dudding TE, Braye SG, Groombridge C, Meldrum C, Spigelman AD, et al., 'Can a familial gastrointestinal tumour syndrome be allelic with Waardenburg syndrome?', Clinical Genetics, 79 554-560 (2011) [C3]
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2011 |
Talseth-Palmer B, Brenne IS, Ashton KA, Evans T-J, McPhillips M, Groombridge C, et al., 'Colorectal cancer susceptibility loci on chromosome 8q23.3 and 11q23.1 as modifiers for disease expression in lynch syndrome', Journal of Medical Genetics, 48 279-284 (2011) [C1]
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Nova |
2011 |
Zacharin M, Bajpai A, Chow CW, Catto-Smith A, Stratakis C, Wong-Brown M, Scott R, 'Gastrointestinal polyps in McCune Albright syndrome', Journal of Medical Genetics, 48 458-461 (2011) [C1]
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Nova |
2011 |
O'Gorman C, Freeman S, Taylor BV, Butzkueven H, Broadley SA, Bahlo M, et al., 'Familial recurrence risks for multiple sclerosis in Australia', Journal of Neurology, Neurosurgery and Psychiatry, 82 1351-1354 (2011) [C1]
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Nova |
2011 |
Bailey HD, Armstrong BK, De Klerk NH, Fritschi L, Attia JR, Scott R, et al., 'Exposure to professional pest control treatments and the risk of childhood acute lymphoblastic leukemia', International Journal of Cancer, 129 1678-1688 (2011) [C1]
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Nova |
2011 |
The International Multiple Sclerosis Consortium, Control TWTC, Cox MB, Lechner-Scott J, Scott R, 'Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis', Nature, 476 214-219 (2011) [C1]
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Nova |
2011 |
Baines KJ, Simpson JL, Wood LG, Scott R, Gibson PG, 'Systemic upregulation of neutrophil a-defensins and serine proteases in neutrophilic asthma', Thorax, 66 942-947 (2011) [C1]
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Nova |
2011 |
Baines KJ, Simpson JL, Wood LG, Scott R, Gibson PG, 'Transcriptional phenotypes of asthma defined by gene expression profiling of induced sputum samples', Journal of Allergy and Clinical Immunology, 127 153.e9-160.e9 (2011) [C1]
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Nova |
2011 |
Kiejda KA, Wong-Brown M, Scott R, 'Genetic markers in breast cancer - How far have we come from BRCA1?', Asia-Pacific Journal of Molecular Medicine, 1 1-15 (2011) [C1]
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Nova |
2011 |
Burn J, Gerdes A-M, Macrae F, Mecklin JP, Moeslein G, Olschwang S, et al., 'Long-term effect of aspirin on cancer risk in carriers of hereditary colorectal cancer: An analysis from the CAPP2 randomised controlled trial', Lancet, 378 2081-2087 (2011) [C1]
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Nova |
2011 |
Wong-Brown M, Nordfors C, Mossman D, Pecenpetelovska G, Kiejda KA, Talseth-Palmer B, et al., 'BRIP1, PALB2, and RAD51C mutation analysis reveals their relative importance as genetic susceptibility factors for breast cancer', Breast Cancer Research and Treatment, 127 853-859 (2011) [C1]
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Nova |
2011 |
Yotova V, Lefebvre J-F, Moreau C, Gbeha E, Hovhannesyan K, Bourgeois S, et al., 'An X-linked haplotype of Neandertal origin is present among all non-African populations', Molecular Biology and Evolution, 28 1957-1962 (2011) [C1]
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Nova |
2011 |
Oldmeadow CJ, Riveros RC, Holliday EG, Scott R, Moscato PA, Wang JJ, et al., 'Sifting the wheat from the chaff: Prioritizing GWAS results by identifying consistency across analytical methods', Genetic Epidemiology, 35 745-754 (2011) [C1]
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Nova |
2011 |
Avery-Kiejda KA, Wong MW, Scott RJ, 'Genetic Markers in Breast Cancer- How Far Have We Come from BRCA1?', MEDICINE AND HEALTH-KUALA LUMPUR, 6 1-24 (2011)
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2011 |
Milne E, Royle JA, Bennett LC, De Klerk NH, Bailey HD, Bower C, et al., 'Maternal consumption of coffee and tea during pregnancy and risk of childhood ALL: Results from an Australian case-control study', Cancer Causes & Control, 22 207-218 (2011) [C1]
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Nova |
2011 |
Maguire JM, Thakkinstian A, Levi CR, Lincz L, Bisset L, Sturm J, et al., 'Impact of COX-2 rs5275 and rs20417 and GPIIIa rs5918 polymorphisms on 90-day ischemic stroke functional outcome: A novel finding', Journal of Stroke and Cerebrovascular Diseases, 20 134-144 (2011) [C1]
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Nova |
2011 |
Gwas Consortium, Henskens FA, Loughland CM, Michie PT, Schall UA, Scott R, 'Genome-wide association study identifies five new schizophrenia loci', Nature Genetics, 43 969-U77 (2011) [C1]
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Nova |
2011 |
Australian Ntl Endometrial Cancer Study Group, Scott R, Ashton KA, Proietto AM, Otton GR, Ntl Study Of Endometrical Cancer Genetics Group, 'Genome-wide association study identifies a common variant associated with risk of endometrial cancer', Nature Genetics, 43 451-455 (2011) [C1]
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Nova |
2011 |
Khor CC, Davila S, Breunis WB, Lee YC, Shimizu C, Wright VJ, et al., 'Genome-wide association study identifies FCGR2A as a susceptibility locus for Kawasaki disease', Nature Genetics, 43 1241-1248 (2011) [C1]
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Nova |
2010 |
Dymerska D, Serrano-Fernandez P, Suchy J, Plawski A, Slomski R, Kaklewski K, et al., 'Combined iPLEX and TaqMan assays to screen for 45 common mutations in Lynch Syndrome and FAP patients', Journal of Molecular Diagnostics, 12 82-90 (2010) [C1]
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Nova |
2010 |
Attia JR, Thakkinstian A, McElduff P, Milne E, Dawson S, Scott R, et al., 'Detecting genotyping error using measures of degree of Hardy-Weinberg disequilibrium', Statistical Applications in Genetics and Molecular Biology, 9 17 (2010) [C1]
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Nova |
2010 |
Ikram MK, Xueling S, Jensen RA, Cotch MF, Hewitt AW, Ikram MA, et al., 'Four Novel Loci (19q13, 6q24, 12q24, and 5q14) influence the microcirculation In Vivo', Plos Genetics, 6 1-12 (2010) [C1]
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Nova |
2010 |
Talseth-Palmer B, McPhillips M, Groombridge C, Spigelman A, Scott R, 'MSH6 and PMS2 mutation positive Australian Lynch syndrome families: Novel mutations, cancer risk and age of diagnosis of colorectal cancer', Hereditary Cancer in Clinical Practice, 8 1-10 (2010) [C1]
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Nova |
2010 |
Proietto AM, Otton GR, Symonds IM, McEvoy MA, Attia JR, Gilbert M, et al., 'Polymorphisms in genes of the steroid hormone biosynthesis and metabolism pathways and endometrial cancer risk', Cancer Epidemiology, 34 328-337 (2010) [C1]
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Nova |
2010 |
Jensen CJ, Stankovich J, Van der Walt A, Bahlo M, Taylor BV, van der Mei IAF, et al., 'Multiple Sclerosis Susceptibility-Associated SNPs Do Not Influence Disease Severity Measures in a Cohort of Australian MS Patients', PLOS ONE, 5 (2010) [C1]
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Nova |
2010 |
Cox MB, Cairns MJ, Gandhi KS, Carroll AP, Moscovis CC, Stewart GJ, et al., 'MicroRNAs miR-17 and miR-20a inhibit T cell activation genes and are under-expressed in MS whole blood', Plos One, 5 e12132 (2010) [C1]
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Nova |
2010 |
Riveros RC, Mellor D, Gandhi KS, McKay FC, Cox MB, Berretta RE, et al., 'A transcription factor map as revealed by a genome-wide gene expression analysis of whole-blood mRNA transcriptome in multiple sclerosis', Plos One, 5 1-28 (2010) [C1]
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Nova |
2010 |
Tomlinson IPM, Dunlop M, Campbell H, Zanke B, Gallinger S, Hudson T, et al., 'COGENT (COlorectal cancer GENeTics): an international consortium to study the role of polymorphic variation on the risk of colorectal cancer (vol 102, pg 447, 2010)', BRITISH JOURNAL OF CANCER, 102 455-455 (2010)
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2010 |
Loughland CM, Draganic D, McCabe KL, Richards JM, Nasir MA, Allen J, et al., 'Australian Schizophrenia Research Bank: A database of comprehensive clinical, endophenotypic and genetic data for aetiological studies of schizophrenia', Australian and New Zealand Journal of Psychiatry, 44 1029-1035 (2010) [C1]
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Nova |
2010 |
Field J, Browning SR, Johnson LJ, Danoy P, Varney MD, Tait BD, et al., 'A polymorphism in the HLA-DPB1 gene is associated with susceptibility to multiple sclerosis', PLoS ONE, 5 (2010) [C1]
We conducted an association study across the human leukocyte antigen (HLA) complex to identify loci associated with multiple sclerosis (MS). Comparing 1927 SNPs in 1618 MS cases a... [more]
We conducted an association study across the human leukocyte antigen (HLA) complex to identify loci associated with multiple sclerosis (MS). Comparing 1927 SNPs in 1618 MS cases and 3413 controls of European ancestry, we identified seven SNPs that were independently associated with MS conditional on the others (each P=4×10-6). All associations were significant in an independent replication cohort of 2212 cases and 2251 controls (P=0:001) and were highly significant in the combined dataset (P=6 × 10-8). The associated SNPs included proxies for HLA-DRB1*15:01 and HLA-DRB1*03:01, and SNPs in moderate linkage disequilibrium (LD) with HLA-A*02:01, HLA-DRB1*04:01 and HLA-DRB1*13:03. We also found a strong association with rs9277535 in the class II gene HLA-DPB1 (discovery set P = 9 × 10-9, replication set P = 7 × 10-4, combined P=2 × 10-10). HLA-DPB1 is located centromeric of the more commonly typed class II genes HLA-DRB1, -DQA1 and -DQB1. It is separated from these genes by a recombination hotspot, and the association is not affected by conditioning on genotypes at DRB1, DQA1 and DQB1. Hence rs9277535 represents an independent MS-susceptibility locus of genome-wide significance. It is correlated with the HLA-DPB1*03:01 allele, which has been implicated previously in MS in smaller studies. Further genotyping in large datasets is required to confirm and resolve this association. © 2010 Field et al.
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Nova |
2010 |
Bowden NA, Ashton KA, Kiejda KA, Zhang XD, Hersey P, Scott R, 'Nucleotide excision repair gene expression after cisplatin treatment in melanoma', Cancer Research, 70 7918-7926 (2010) [C1]
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Nova |
2010 |
Holliday EG, Scott R, Attia JR, 'Evidence-based medicine in the era of biomarkers: Teaching a new dog old tricks?', Clinical Pharmacology and Therapeutics, 88 740-742 (2010) [C2]
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2010 |
Milne E, Royle JA, Miller M, Bower C, De Klerk NH, Bailey HD, et al., 'Maternal folate and other vitamin supplementation during pregnancy and risk of acute lymphoblastic leukemia in the offspring', International Journal of Cancer, 126 2690-2699 (2010) [C1]
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Nova |
2010 |
Jakubowska A, Gronwald J, Menkiszak J, Gorski B, Huzarski T, Byrski T, et al., 'BRCA1-associated breast and ovarian cancer risks in Poland: No association with commonly studied polymorphisms', Breast Cancer Research and Treatment, 119 201-211 (2010) [C1]
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Nova |
2010 |
Dudding TE, Lawrence O, Winship I, Froyen G, Vandewalle J, Scott R, Shelling AN, 'Array comparative genomic hybridization for the detection of submicroscopic copy number variations of the X chromosome in women with premature ovarian failure', Human Reproduction, 25 3159-3160 (2010) [C3]
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2010 |
McEvoy MA, Smith WT, D'Este CA, Duke JM, Peel R, Schofield PW, et al., 'Cohort Profile: The Hunter Community Study', International Journal of Epidemiology, 39 1452-1463 (2010) [C1]
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Nova |
2010 |
Baines KJ, Simpson JL, Bowden NA, Scott R, Gibson PG, 'Differential gene expression and cytokine production from neutrophils in asthma phenotypes', European Respiratory Journal, 35 522-531 (2010) [C1]
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Nova |
2010 |
Scott R, 'Genetics of colorectal cancers', VIRCHOWS ARCHIV, 457 101-102 (2010) [C1] |
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2010 |
Gandhi KS, McKay FC, Cox MB, Riveros RC, Armstrong N, Heard RN, et al., 'The multiple sclerosis whole blood mRNA transcriptome and genetic associations indicate dysregulation of specific T cell pathways in pathogenesis', Human Molecular Genetics, 19 2134-2143 (2010) [C1]
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Nova |
2010 |
Out AA, Tops CMJ, Nielsen M, Weiss MM, Van Minderhout IJHM, Fokkema IFAC, et al., 'Leiden Open Variation Database of the MUTYH Gene', Human Mutation, 31 1205-1215 (2010) [C1]
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Nova |
2010 |
Booth DR, Heard RN, Stewart GJ, Cox M, Scott R, Lechner-Scott J, et al., 'Lack of support for association between the KIF1B rs10492972[C] variant and multiple sclerosis', Nature Genetics, 42 469-470 (2010) [C3]
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2010 |
Cox AJ, Gleeson M, Pyne DB, Callister R, Fricker PA, Scott R, 'Cytokine gene polymorphisms and risk for Upper Respiratory Symptoms in highly-trained athletes', Exercise Immunology Review, 16 8-21 (2010) [C1]
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Nova |
2010 |
Scott R, 'Have the roles of two functional polymorphisms in breast cancer, R72P in P53 and MDM2-309 in MDM2, become clearer?', Breast Cancer Research, 12 1-3 (2010) [C3]
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2010 |
Esposito F, Patsopoulos NA, Cepok S, Kockum I, Leppa V, Booth DR, et al., 'IL12A, MPHOSPH9/CDK2AP1 and RGS1 are novel multiple sclerosis susceptibility loci', Genes and Immunity, 11 397-405 (2010) [C1]
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Nova |
2010 |
Ashton KA, Proietto AM, Otton GR, Symonds IM, McEvoy MA, Attia JR, Scott R, 'Toll-Like Receptor (TLR) and Nucleosome-binding Oligomerization Domain (NOD) gene polymorphisms and endometrial cancer risk', BMC Cancer, 10 1-7 (2010) [C1]
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Nova |
2010 |
Mossman D, Kim K-T, Scott R, 'Demethylation by 5-aza-2'-deoxycytidine in colorectal cancer cells targets genomic DNA whilst promoter CpG island methylation persists', BMC Cancer, 10 1-10 (2010) [C1]
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Nova |
2010 |
Trubicka J, Grabowska-Klujszo E, Suchy J, Masojc B, Serrano-Fernandez P, Kurzawski G, et al., 'Variant alleles of the CYP1B1 gene are associated with colorectal cancer susceptibility', BMC Cancer, 10 1-6 (2010) [C1]
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Nova |
2009 |
Ashton KA, Proietto AM, Otton GR, Symonds IM, McEvoy MA, Attia JR, et al., 'Estrogen receptor polymorphisms and the risk of endometrial cancer', BJOG: An International Journal of Obstetrics and Gynaecology, 116 1053-1061 (2009) [C1]
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Nova |
2009 |
Whitehall V, Tran K, Umapathy A, Grieu F, Hewitt C, Evans T-J, et al., 'A Multicenter Blinded Study to Evaluate KRAS Mutation Testing Methodologies in the Clinical Setting', JOURNAL OF MOLECULAR DIAGNOSTICS, 11 543-552 (2009) [C1]
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2009 |
Gapska P, Scott R, Serrano-Fernandez P, Huzarski T, Byrski T, Kladny J, et al., 'Vitamin D receptor variants and breast cancer risk in the Polish population', Breast Cancer Research and Treatment, 115 629-633 (2009) [C1]
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Nova |
2009 |
Ashton KA, Proietto AM, Otton GR, Symonds IM, Scott R, 'Genetic variants in MUTYH are not associated with endometrial cancer risk', Hereditary Cancer in Clinical Practice, 7 1-5 (2009) [C1]
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Nova |
2009 |
Lubinski J, Sijmons RH, Scott R, 'Hereditary cancer in clinical practice transfers to BioMed Central', Hereditary Cancer in Clinical Practice, 7 Article 1 (2009) [C3]
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Nova |
2009 |
Gapska P, Scott R, Serrano-Fernandez P, Mirecka A, Rassoud I, Gorski B, et al., 'Vitamin D receptor variants and the malignant melanoma risk: A population-based study', Cancer Epidemiology, 33 103-107 (2009) [C1]
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Nova |
2009 |
Stankovich J, Butzkueven H, Marriott M, Chapman C, Tubridy N, Tait BD, et al., 'HLA-DRB1 associations with disease susceptibility and clinical course in Australians with multiple sclerosis', TISSUE ANTIGENS, 74 17-21 (2009)
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2009 |
Milne E, Royle JA, De Klerk NH, Blair E, Bailey H, Cole C, et al., 'Fetal growth and risk of childhood acute lymphoblastic leukemia: Results from an Australian case-control study', American Journal of Epidemiology, 170 221-228 (2009) [C1]
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Nova |
2009 |
Shi Z, Johnstone DM, Talseth-Palmer B, Evans T-J, Spigelman AD, Groombridge C, et al., 'Haemochromatosis HFE gene polymorphisms as potential modifiers of hereditary nonpolyposis colorectal cancer risk and onset age', International Journal of Cancer, 125 78-83 (2009) [C1]
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Nova |
2009 |
Weidenhofer JC, Scott R, Tooney PA, 'Investigation of the expression of genes affecting cytomatrix active zone function in the amygdala in schizophrenia: Effects of antipsychotic drugs', Journal of Psychiatric Research, 43 282-290 (2009) [C1]
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Nova |
2009 |
Tomlinson IPM, Dunlop M, Campbell H, Zanke B, Gallinger S, Hudson T, et al., 'COGENT (COlorectal cancer GENeTics): an international consortium to study the role of polymorphic variation on the risk of colorectal cancer', British Journal of Cancer, 102 447-454 (2009) [C1]
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Nova |
2009 |
Ashton KA, Proietto AM, Otton GR, Symonds IM, McEvoy MA, Attia JR, et al., 'Polymorphisms in TP53 and MDM2 combined are associated with high grade endometrial cancer', Gynecologic Oncology, 113 109-114 (2009) [C1]
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Nova |
2009 |
Attia J, Ioannidis JPA, Thakkinstian A, McEvoy M, Scott RJ, Minelli C, et al., 'How to Use an Article About Genetic Association: A: Background Concepts (vol 301, pg 74, 2009)', JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION, 301 1024-1024 (2009) [C3]
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2009 |
Attia JR, Ioannidis JPA, Thakkinstian A, McEvoy MA, Scott R, Minelli C, et al., 'How to use an article about genetic association A: Background concepts', JAMA: Journal of the American Medical Association, 301 74-81 (2009) [C1]
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Nova |
2009 |
Attia JR, Ioannidis JPA, Thakkinstian A, McEvoy MA, Scott R, Minelli C, et al., 'How to use an article about genetic association B: Are the results of the study valid?', JAMA: Journal of the American Medical Association, 301 191-197 (2009) [C1]
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Nova |
2009 |
Attia JR, Ioannidis JPA, Thakkinstian A, McEvoy MA, Scott R, Minelli C, et al., 'How to use an article about genetic association C: What are the results and will they help me in caring for my patients?', JAMA: Journal of the American Medical Association, 301 304-308 (2009) [C1]
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Nova |
2009 |
Lubinski J, Korzen M, Gorski B, Cybulski C, Debniak T, Jakubowska A, et al., 'Genetic contribution to all cancers: The first demonstration using the model of breast cancers from Poland stratified by age at diagnosis and tumour pathology', Breast Cancer Research and Treatment, 114 121-126 (2009) [C1]
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Nova |
2009 |
Baines KJ, Simpson JL, Scott R, Gibson PG, 'Immune responses of airway neutrophils are impaired in asthma', Experimental Lung Research, 35 554-569 (2009) [C1]
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Nova |
2009 |
Simpson JL, Baines KJ, Boyle MJ, Scott R, Gibson PG, 'Oncostatin M (OSM) is increased in asthma with incompletely reversible airflow obstruction', Experimental Lung Research, 35 781-794 (2009) [C1]
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Nova |
2009 |
Umapathy A, Whitehall V, Tran K, Grieu F, Hewitt C, Evans TJ, et al., 'A multicentre study to evaluate k-ras mutation testing methodologies in the clinical setting', JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, 24 A240-A240 (2009) [E3] |
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Nova |
2009 |
Reeves SG, Meldrum C, Groombridge C, Spigelman AD, Suchy J, Kurzawski G, et al., 'MTHFR 677 C\T and 1298 A\C polymorphisms and the age of onset of colorectal cancer in hereditary nonpolyposis colorectal cancer', European Journal of Human Genetics, 17 629-635 (2009) [C1]
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Nova |
2009 |
Kaput J, Cotton RGH, Hardman L, Watson M, Aqeel AIA, Al-Aama JY, et al., 'Planning the Human Variome Project: The Spain report', Human Mutation, 30 496-510 (2009) [C1]
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Nova |
2009 |
Bahlo M, Booth DR, Broadley SA, Brown MA, Foote SJ, Griffiths LR, et al., 'Genome-wide association study identifies new multiple sclerosis susceptibility loci on chromosomes 12 and 20', Nature Genetics, 41 824-828 (2009) [C1]
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Nova |
2009 |
Kladny J, Suchy J, Klujszo-Grabowska E, Kacperski T, Scott R, Kurzawski G, Lubinski J, 'Clinical characteristics of tumors derived from colorectal cancer patients who harbor the Tumor Necrosis Factor beta-1031T/T and NOD2 3020insC polymorphism', Cancer Epidemiology, 33 161-163 (2009) [C1]
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2009 |
Cotton RGH, Al Aqeel AI, Al-Mulla F, Carrera P, Claustres M, Ekong R, et al., 'Capturing all disease-causing mutations for clinical and research use: Toward an effortless system for the Human Variome Project', Genetics in Medicine, 11 843-849 (2009) [C1]
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Nova |
2009 |
Talseth-Palmer B, Bowden NA, Meldrum C, Nicholl J, Thompson E, Friend K, et al., 'A 1q44 deletion, paternal UPD of chromosome 2 and a deletion due to a complex translocation detected in children with abnormal phenotypes using new SNP array technology', Cytogenetic and Genome Research, 124 94-101 (2009) [C1]
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Nova |
2008 |
Simpson JL, Powell H, Boyle MJ, Scott R, Gibson PG, 'Clarithromycin targets neutrophilic airway inflammation in refractory asthma', American Journal of Respiratory and Critical Care Medicine, 177 148-155 (2008) [C1]
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Nova |
2008 |
Kiejda KA, Zhang XD, Adams LJ, Scott R, Vojtesek B, Lane DP, Hersey P, 'Small molecular weight variants of p53 are expressed in human melanoma cells and are induced by the DNA-damaging agent cisplatin', Clinical Cancer Research, 14 1659-1668 (2008) [C1]
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Nova |
2008 |
Bowden NA, Scott R, Tooney PA, 'Altered gene expression in the superior temporal gyrus in schizophrenia', BMC Genomics, 9 1-12 (2008) [C1]
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Nova |
2008 |
Jakubowska A, Menkiszak J, Gorski B, Huzarski T, Byrski T, Benner A, et al., 'Ovarian cancer risk in Polish BRCA1 mutation carriers is not associated with the prohibitin 3' untranslated region polymorphism', BMC Cancer, 8 1-5 (2008) [C1]
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Nova |
2008 |
Suchy J, Klujszo-Grabowska E, Kladny J, Cybulski C, Wokolorczyk D, Szymanska-Pasternak J, et al., 'Inflammatory response gene polymorphisms and their relationship with colorectal cancer risk', BMC Cancer, 8 1-7 (2008) [C1]
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Nova |
2008 |
Ashton KA, Proietto AM, Otton GR, Symonds IM, McEvoy MA, Attia JR, et al., 'The influence of the Cyclin D1 870 G\A polymorphism as an endometrial cancer risk factor', BMC Cancer, 8 1-6 (2008) [C1]
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Nova |
2008 |
Dudding TE, Heron J, Thakkinstian A, Nurk E, Golding J, Pembrey M, et al., 'Factor V Leiden is associated with pre-eclampsia but not with fetal growth restriction: A genetic association study and meta-analysis', Journal of Thrombosis and Haemostasis, 6 1868-1875 (2008) [C1]
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Nova |
2008 |
Talseth-Palmer B, Bowden NA, Hill A, Meldrum C, Scott R, 'Whole genome amplification and its impact on CGH array profiles', BMC Research Notes, 1 108 (2008) [C1]
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Nova |
2008 |
Scott R, Crooks R, Meldrum C, 'Gene symbol: STK11. Disease: Peutz-Jeghers Syndrome.', Human genetics, 124 300 (2008) [C3]
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2008 |
Debniak T, Van De Wetering T, Scott R, Nagay L, Cybulski C, Gorski B, et al., 'Low prevalence of CDKN2A/ARF mutations among early-onset cancers of breast, pancreas and malignant melanoma in Poland', European Journal of Cancer Prevention, 17 389-391 (2008) [C1]
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Nova |
2008 |
Froyen G, Corbett M, Vandewalle J, Jarvela I, Lawrence O, Meldrum C, et al., 'Submicroscopic duplications of the hydroxysteroid dehydrogenase HSD17B10 and the E3 ubiquitin ligase HUWE1 are associated with mental retardation', American Journal of Human Genetics, 82 432-443 (2008) [C1]
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Nova |
2008 |
Foster RC, Byrnes EM, Meldrum C, Griffith R, Ross G, Upjohn E, et al., 'Association of paediatric mastocytosis with a polymorphism resulting in an amino acid substitution (M541L) in the transmembrane domain of c-KIT', British Journal of Dermatology, 159 1160-1169 (2008) [C1]
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Nova |
2008 |
Zlowocka E, Cybulski C, Gorski B, Debniak T, Slojewski M, Wokolorczyk D, et al., 'Germline mutations in the CHEK2 kinase gene are associated with an increased risk of bladder cancer', International Journal of Cancer, 122 583-586 (2008) [C1]
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Nova |
2008 |
Talseth-Palmer B, Ashton KA, Meldrum C, Suchy J, Kurzawski G, Lubinski J, Scott R, 'Aurora-A and Cyclin D1 polymorphisms and the age of onset of colorectal cancer in hereditary nonpolyposis colorectal cancer', International Journal of Cancer, 122 1273-1277 (2008) [C1]
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Nova |
2008 |
Reeves SG, Rich D, Meldrum CJ, Colyvas KJ, Kurzawski G, Suchy J, et al., 'IGF1 is a modifier of disease risk in hereditary non-polyposis colorectal cancer', International Journal of Cancer, 123 1339-1343 (2008) [C1]
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Nova |
2008 |
Burn J, Bishop T, Mecklin J-P, Macrae F, Moslein G, Olschwang S, et al., 'Effect of aspirin or resistant starch on colorectal neoplasia in the Lynch syndrome', New England Journal of Medicine, 359 2567-2578 (2008) [C1]
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Nova |
2008 |
Jaworowska E, Serrano-Fernandez P, Tarnowska C, Lubinski J, Brzosko M, Flicinski J, et al., 'Familial association of laryngeal, lung, stomach and early-onset breast cancer', Breast Cancer Research and Treatment, 112 359-361 (2008) [C1]
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Nova |
2008 |
Reeves SG, Mossman D, Meldrum CJ, Kurzawski G, Suchy J, Lubinski J, Scott R, 'The-149C \ T SNP within the Delta DNMT3B gene, is not associated with early disease onset in hereditary non-polyposis colorectal cancer', Cancer Letters, 265 39-44 (2008) [C1]
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Nova |
2008 |
Jakubowska A, Gronwald J, Menklszak J, Gorski B, Huzarski T, Byrski T, et al., 'The VEGF_936_C \ T 3 ' UTR polymorphism reduces BRCA1-associated breast cancer risk in Polish women', Cancer Letters, 262 71-76 (2008) [C1]
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Nova |
2008 |
Debniak B, Kowalska E, Jakubowska A, Gronwald J, Wokolorczyk D, Maleszka R, et al., 'Common variants of DNA repair genes and malignant melanoma', European Journal of Cancer, 44 110-114 (2008) [C1]
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Nova |
2008 |
Beveridge NJ, Tooney PA, Carroll AP, Gardiner EJ, Bowden NA, Scott R, et al., 'Dysregulation of miRNA 181b in the temporal cortex in schizophrenia', Human Molecular Genetics, 17 1156-1168 (2008) [C1]
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Nova |
2008 |
Scott R, 'Variable phenotypic expression in HNPCC and the search for modifier genes', European Journal of Human Genetics, 16 531-532 (2008) [C2]
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Nova |
2007 |
Jaworowska E, Serrano-Fernandez P, Tarnowska C, Lubinski J, Kram A, Masojc B, et al., 'Clinical and epidemiological features of familial laryngeal cancer in Poland', Cancer Detection and Prevention, 31 270-275 (2007) [C1]
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2007 |
Bowden NA, Scott R, Tooney PA, 'Altered expression of regulator of G-protein signalling 4 (RGS4) mRNA in the superior temporal gyrus in schizophrenia', Schizophrenia Research, 89 165-168 (2007) [C1]
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2007 |
The International Breast Cancer Study Group, Forbes JF, 'Effects of a treatment gap during adjuvant chemotherapy in node-positive breast cancer: Results of International Breast Cancer Study Group (IBCSG) Trials 13-93 and 14-93', Annals of Oncology, 18 1177-1184 (2007) [C1]
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2007 |
Attia JR, Thakkinstian A, Wang Y, Lincz L, Parsons MW, Sturm J, et al., 'The PAI-1 4G/5G gene polymorphism and ischemic stroke: An association study and meta-analysis', Journal of Stroke and Cerebrovascular Diseases, 16 173-179 (2007) [C1]
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2007 |
Jakubowska A, Gronwald J, Menkiszak J, Gorski B, Huzarski T, Byrski T, et al., 'The RAD51 135 G \ C polymorphism modifies breast cancer and ovarian cancer risk in Polish BRCA1 mutation carriers', Cancer Epidemiology Biomarkers & Prevention, 16 270-275 (2007) [C1]
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2007 |
Lubinski J, Korzen M, Gorski B, Cybulski C, Debniak T, Jakubowska A, et al., 'Breast cancer susceptibility genes', Journal of the Balkan Union of Oncology, 12 S23-S29 (2007) [C1]
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2007 |
Scott R, 'Dear Readers', Hereditary Cancer in Clinical Practice, 5 1 (2007) |
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2007 |
Scott RJ, 'Dear readers', Hereditary Cancer in Clinical Practice, 5 181 (2007) |
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2007 |
Mhaidat NM, Zhang XD, Allen J, Kiejda KA, Scott R, Hersey P, 'Temozolomide induces senescence but not apoptosis in human melanoma cells', British Journal of Cancer, 97 1225-1233 (2007) [C1]
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2007 |
Bowden NA, Croft A, Scott R, 'Gene expression profiling in familial adenomatous polyposis adenomas and desmoid disease', Hereditary Cancer in Clinical Practice, 5 79-96 (2007) [C1]
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2007 |
Kairupan C, Scott R, 'Base excision repair and the role of MUTYH', Hereditary Cancer in Clinical Practice, 5 199-209 (2007) [C1]
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2007 |
Scott R, 'Response to 'Variability in the clinical phenotype among families with HNPCC': The potential importance of the location of the mutation in the gene by Dr. Prathap Bandipalliant', International Journal of Cancer, 120 2278 (2007) [C3]
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2007 |
Talseth-Palmer B, Meldrum C, Suchy J, Kurzawski G, Lubinski J, Scott R, 'MDM2 SNP309 T \ G alone or in combination with the TP53 R72P polymorphism does not appear to influence disease expression and age of diagnosis of colorectal cancer in HNPCC patients', International Journal of Cancer, 120 563-565 (2007) [C1]
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2007 |
Jakubowska A, Gronwald J, Menkiszak J, Gorski B, Huzarski T, Byrski T, et al., 'Integrin 3 Leu33Pro polymorphism increases BRCA1-associated ovarian cancer risk', Journal of Medical Genetics, 44 408-411 (2007) [C1]
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2007 |
Easton DF, Search Collaborators Including, Forbes JF, 'Genome-wide association study identifies novel breast cancer susceptibility loci', Nature, 447 1087-1093 (2007) [C1]
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Nova |
2007 |
Talseth-Palmer B, Meldrum C, Suchy J, Kurzawski G, Lubinski J, Scott R, 'Lack of association between genetic polymorphisms in cytokine genes and disease expression in patients with hereditary non-polyposis colorectal cancer', Scandinavian Journal of Gastroenterology, 42 628-632 (2007) [C1]
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2007 |
Simpson JL, Grissell TV, Douwes J, Scott R, Boyle MJ, Gibson PG, 'Innate immune activation in neutrophilic asthma and bronchiectasis', Thorax, 62 211-218 (2007) [C1]
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2007 |
Jakubowska A, Gronwald J, Menkiszak J, Go B, Huzarski T, Byrski T, et al., 'Methylenetetrahydrofolate reductase polymorphisms modify BRCA1-associated breast and ovarian cancer risks', Breast Cancer Research and Treatment, 104 299-308 (2007) [C1]
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2007 |
Jakubowska A, Gronwald J, Gorski B, Huzarski T, Byrski T, Benner A, et al., 'The 3 ' untranslated region C \ T polymorphism of prohibitin is a breast cancer risk modifier in Polish women carrying a BRCA1 mutation', Breast Cancer Research and Treatment, 104 67-74 (2007) [C1]
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2007 |
Matyjasik J, Cybulski C, Masojc B, Jakubowska A, Serrano-Fernandez P, Gorski B, et al., 'CYP1B1 and predisposition to breast cancer in Poland', Breast Cancer Research and Treatment, 106 383-388 (2007) [C1]
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2006 |
Hearle N, Schumacher V, Menko FH, Olschwang S, Boardman LA, Gille JJP, et al., 'STKII status and intussusception risk in Peutz-Jeghers syndrome', Journal of Medical Genetics, 43 41-43 (2006) [C1]
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2006 |
Reeves SG, Meldrum C, Scott R, 'Re: IGF-1 gene polymorphism and risk for hereditary nonpolyposis colorectal cancer (Letter)', Journal of the National Cancer Institute, 98 1664-1665 (2006) [C3]
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Nova |
2006 |
Weidenhofer JC, Bowden NA, Scott R, Tooney PA, 'Altered gene expression in the amygdala in schizophrenia: Up-regulation of genes located in the cytomatrix active zone', Molecular and Cellular Neuroscience, 31 243-250 (2006) [C1]
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2006 |
Talseth-Palmer B, Meldrum C, Suchy J, Kurzawski G, Lubinski J, Scott R, 'Age of diagnosis of colorectal cancer in HNPCC patients is more complex than that predicted by R72P polymorphism in TP53', International Journal of Cancer, 118 2479-2484 (2006) [C1]
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2006 |
Lener MR, Oszutowska D, Castaneda J, Kurzawski G, Suchy J, Nej-Wolosiak K, et al., 'Prevalence of the NOD32 3020insC mutation in aggregations of breast and lung cancer', Breast Cancer Research and Treatment, 95 141-145 (2006) [C1]
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2006 |
Jaworowska E, Masojc B, Tarnowska C, Brzosko M, Flicinski J, Serrano-Fernandez P, et al., 'Association between early-onset breast and laryngeal cancers', Breast Cancer Research and Treatment, 97 215-219 (2006) [C1]
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2006 |
Debniak T, Scott R, Huzarski T, Byrski T, Masojc B, Van De Wetering T, et al., 'XPD common variants and their association with melanoma and breast cancer risk', Breast Cancer Research and Treatment, 98 209-215 (2006) [C1]
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2006 |
Masojc B, Mierzejewski M, Cybulski C, Van De Wetering T, Debniak T, Gorski B, et al., 'Cancer familial aggregation (CFA) and G446A polymorphism in ARLTS1 gene', Breast Cancer Research and Treatment, 99 59-62 (2006) [C1]
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2006 |
Dedniak T, Scott R, Huzarski T, Byrski T, Rozmiarek A, Debniak B, et al., 'CDKN2A common variant and multi-organ cancer risk - a population-based study (Short report)', International Journal of Cancer, 118 3180-3182 (2006) [C1]
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2006 |
Moscovis SM, Gordon AE, Al Madani OM, Gleeson M, Scott R, Roberts-Thomson JM, et al., 'IL6 G-174C Associated With Sudden Infant Death Syndrome in a Caucasian Australian Cohort', Human Immunology, 67 819-825 (2006) [C1]
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2006 |
Chow E, Meldrum CJ, Crooks R, Macrae FA, Spigelman AD, Scott RJ, 'An updated mutation spectrum in an Australian series of Peutz-Jeghers Syndrome patients provides further evidence for only one gene locus', JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, 21 A262-A262 (2006) |
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2006 |
Bowden NA, Weidenhofer JC, Scott R, Schall U, Todd J, Michie PT, Tooney PA, 'Preliminary investigation of gene expression profiles in peripheral blood lymphocytes in schizophrenia', Schizophrenia Research, 82 175-183 (2006) [C1]
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Nova |
2006 |
Hitchins M, Suter C, Wong J, Cheong K, Hawkins N, Leggett B, et al., 'Germline epimutations of APC are not associated with inherited colorectal polyposis (Letter)', Gut, 55 586-587 (2006) [C3]
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2006 |
Debniak T, Scott R, Masojc B, Serrano-Fernandez P, Huzarski T, Byrski T, et al., 'MC1R common variants, CDKN2A and their association with melanoma and breast cancer risk', International Journal of Cancer, 119 2597-2602 (2006) [C1]
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2006 |
Simpson JL, Scott R, Boyle MJ, Gibson PG, 'Inflammatory subtypes in asthma: Assessment and identification using induced sputum', Respirology, 11 54-61 (2006) [C1]
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2006 |
Debniak T, Scott RJ, Huzarski T, Byrski T, Rozmiarek A, Debniak B, et al., 'CDKN2A common variant and multi-organ cancer risk - a population-based study.(vol 118, pg 3180, 2006)', INTERNATIONAL JOURNAL OF CANCER, 119 2502-2502 (2006)
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2006 |
Milne E, van Bockxmeer FM, Robertson L, Brisbane JM, Ashton LJ, Scott RJ, 'Buccal DNA collection: comparison of buccal swabs with FTA cards (vol 15, pg 816, 2006)', CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION, 15 1056-1056 (2006) |
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2006 |
Milne E, Van Bockxmeer FM, Robertson L, Brisbane JM, Ashton LJ, Scott R, Armstrong BK, 'Buccal DNA collection: Comparison of buccal swabs with FTA cards (short communication)', Cancer Epidemiology Biomarkers & Prevention, 15 816-819 (2006) [C1]
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2006 |
Ashton KA, Meldrum CJ, McPhillips ML, Suchy J, Kurzawski G, Lubinski J, Scott R, 'The association of the COMT V158M polymorphism with endometrial/ovarian cancer in HNPCC families adhering to the Amsterdam criteria', Hereditary Cancer in Clinical Practice, 4 94-102 (2006) [C1]
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2006 |
Mossman D, Scott R, 'Epimutations, inheritance and causes of aberrant DNA methylation in cancer', Hereditary Cancer in Clinical Practice, 4 75-80 (2006) [C1]
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2006 |
Bowden NA, Tooney PA, Scott R, 'Gene expression profiling of xeroderma pigmentosum', Hereditary Cancer in Clinical Practice, 4 103-110 (2006) [C1]
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Nova |
2006 |
Scott RJ, Moscovis SM, Hall ST, Gleeson M, Roberts-Thompson J, Blackwell CC, 'The influence of infection on cytokine gene polymorphisms in evolution', Before Farming, (2006) [C2]
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2006 |
Milne E, Van Bockxmeer FM, Robertson L, Brisbane JM, Ashton LJ, Scott RJ, et al., 'Erratum: Buccal DNA collection: Comparison of buccal swabs with FTA cards (Cancer Epidemiology Biomarkers and Prevention (April 2006) 15 (816-819))', Cancer Epidemiology Biomarkers and Prevention, 15 1056 (2006)
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2006 |
D bniak T, Cybulski C, Kurzawski G, Górski B, Huzarski T, Byrski T, et al., 'Low-risk genes and multi-organ cancer risk in the Polish population', Hereditary Cancer in Clinical Practice, 4 52-55 (2006)
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2006 |
Scott RJ, 'Hereditary Cancer in Clinical Practice: Editorial', Hereditary Cancer in Clinical Practice, 4 73 (2006) |
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2006 |
Talseth-Palmer B, Meldrum C, Suchy J, Kurzawski G, Lubinski J, Scott R, 'Genetic polymorphisms in xenobiotic clearance genes and their influence on disease expression in hereditary nonpolyposis colorectal cancer patients', Cancer Epidemiology Biomarkers & Prevention, 15 2307-2310 (2006) [C1]
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2006 |
Hearle N, Schumacher V, Menko FH, Olschwang S, Boardman LA, Gille JJP, et al., 'Frequency and spectrum of cancers in the Peutz-Jeghers syndrome', Clinical Cancer Research, 12 3209-3215 (2006) [C1]
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2006 |
Weidenhofer J, Bowden NA, Scott RJ, Tooney PA, 'Dysfunction of genes regulating membrane exocytosis in schizophrenia', AUSTRALIAN AND NEW ZEALAND JOURNAL OF PSYCHIATRY, 40 A129-A129 (2006)
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2006 |
Kurzawski G, Suchy J, Lener M, Klujszo-Grabowska E, Kladny J, Safranow K, et al., 'Germline MSH2 and MLH1 mutational spectrum including large rearrangements in HNPCC families from Poland (update study)', Clinical Genetics, 69 40-47 (2006) [C1]
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2006 |
Chow E, Meldrum CJ, Crooks R, Macrae F, Spigelman AD, Scott R, 'An updated mutation spectrum in an Australian series of PJS patients provides further evidence for only one gene locus', Clinical Genetics, 70 409-414 (2006) [C1]
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2006 |
Suchy J, Kurzawski G, Jakubowska K, Rac ME, Safranow K, Kladny J, et al., 'Frequency and nature of hMSH6 germline mutations in Polish patients with colorectal, endometrial and ovarian cancers (letter)', Clinical Genetics, 70 68-70 (2006) [C3]
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2005 |
Debniak T, Scott R, Huzarski T, Byrski T, Rozmiarek A, Debniak B, et al., 'CDKN2A common variants and their association with melanoma risk: A population-based study', Cancer Research, 65 835-839 (2005) [C1]
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2005 |
Hitchins M, Williams R, Cheong K, Halani N, Lin VAP, Packham D, et al., 'MLH1 Germline Epimutations as a Factor in Hereditary Nonpolyposis Colorectal Cancer', Gastroenterology, 129 1392-1399 (2005) [C1]
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Nova |
2005 |
Weir L, Spigelman AD, Scott R, Kirk J, Zeckendorf S, Sitas F, 'The NSW & ACT Hereditary Cancer Registers', Australian Family Physician, 34 53-57 (2005) [C3]
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2005 |
Blackwell CC, Moscovis SM, Gordon AE, Al Madani OM, Hall S, Gleeson M, et al., 'Cytokine responses and sudden infant death: genetic, developmental, and environmental risk factors', Journal of Leukocyte Biology, 78 1242-1254 (2005) [C1]
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2005 |
Kairupan CF, Meldrum CJ, Crooks R, Milward EA, Spigelman AD, Burgess B, et al., 'Mutation analysis of the MYH gene in an Australian series of colorectal polyposis patients with or without germline APC mutations', International Journal of Cancer, 116 73-77 (2005) [C1]
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Nova |
2005 |
Gronwald J, Jauch A, Cybulski C, Schoell B, Bohm-Steuer B, Lener M, et al., 'Comparison of genomic abnormalities between BRCAX and sporadic breast cancers studied by comparative genomic hybridization', International Journal of Cancer, 114 230-236 (2005) [C1]
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Nova |
2005 |
Scott RJ, 'Hereditary Cancer in Clinical Practice: Editorial', Hereditary Cancer in Clinical Practice, 3 85 (2005) |
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2005 |
Simpson JL, Scott R, Boyle MJ, Gibson PG, 'Differential proteolytic enzyme activity in eosinophilic and neutrophilic asthma', American Journal of Respiratory and Critical Care Medicine, 172 559-565 (2005) [C1]
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Nova |
2005 |
Weber W, Scott R, 'Case report: Familial gastric cancer and chordoma in the same family', Hereditary Cancer in Clinical Practice, 3 81-84 (2005) [C2]
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2005 |
McPhillips M, Meldrum CJ, Scott R, Creegan R, Edkins E, 'Deletion mutations in an Australian series of HNPCC patients', Hereditary Cancer in Clinical Practice, 3 43-47 (2005) [C2]
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2005 |
Ashton KA, Meldrum CJ, McPhillips ML, Kairupan CF, Scott R, 'Frequency of the common MYH mutations (G382D and Y165C) in MMR mutation positive and negative HNPCC patients', Hereditary Cancer in Clinical Practice, 3 65-70 (2005) [C1]
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Nova |
2005 |
Scott R, Meldrum C, 'Missense mutations in cancer predisposing genes: can we make sense of them?', Hereditary Cancer in Clinical Practice, 3 123-127 (2005) [C1]
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2004 |
Marazita ML, Murray JC, Lidral AC, Arcos-Burgos M, Cooper ME, Goldstein T, et al., 'Meta-analysis of 13 genome scans reveals multiple cleft lip/palate genes with novel loci on 9q21 and 2q32-35', American Journal of Human Genetics, 75 161-173 (2004) [C1]
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2004 |
Kurzawski G, Suchy J, Lubinski J, Scott RJ, 'NOD2 and colorectal cancer: Guilt by non-association - Response', CANCER RESEARCH, 64 5525-5526 (2004) |
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Nova |
2004 |
Kurzawski G, Suchy J, Kladny J, Grabowska E, Mierzejewski M, Jakubowska A, et al., 'The NOD2 3020insC Mutation and the Risk of Colorectal Cancer', Cancer Research, 64 1604-1606 (2004) [C1]
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2004 |
Kurzawski G, Suchy J, Lubinski J, Scott R, 'NOD2 and colorectal cancer: guilt by non-association', Cancer Research, 64 5525-5526 (2004) [C1]
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2004 |
Scott R, Meldrum CJ, 'Response to De Vos et al', Clinical Genetics, 66 568 (2004) [C3] |
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2004 |
Thompson E, Meldrum CJ, Crooks R, McPhillips M, Thomas LS, Spigelman AD, Scott R, 'Hereditary non-polyposis colorectal cancer and the role of hPMS2 and hEXO1 mutations', Clinical Genetics, 65 215-225 (2004) [C1]
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2004 |
Lim W, Olschwang S, Keller J, Westerman A, Menko F, Boardman L, et al., 'Relative frequency and morphology of cancers in STK11 mutation carriers', Gastroenterology, 126 1788-1794 (2004) [C1]
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2004 |
Debniak T, Gorski B, Scott R, Cybulski C, Medrek K, Zlowocka E, et al., 'Germline Mutation and Large Deletion Analysis of the CDKN2A and ARF Genes in Families with Multiple Melanoma or an Aggregation of Maligant Melanoma and Breast Cancer', International Journal of Cancer, 110 558-562 (2004) [C1]
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2004 |
Smith CJ, Crock PA, King BR, Meldrum CJ, Scott R, 'Phenotype-Genotype Correlations in a Series of Wolfram Syndrome Families', Diabetes Care, 27 2003-2009 (2004) [C1]
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Nova |
2004 |
Scott R, 'DNA mismatch repair genes and hereditary non-polyposis colorectal cancer', J Gastro Hepatol, 19 465-466 (2004) [C1]
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2004 |
Moscovis SM, Gordon AE, Al Madani OM, Gleeson M, Scott R, Roberts-Thomson JM, et al., 'Interleukin-10 and sudden infant death syndrome', FEMS Immunology and Medical Microbiology, 42 130-138 (2004) [C1]
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2004 |
Moscovis SM, Gordon AE, Hall ST, Gleeson M, Scott R, Roberts-Thomson JM, et al., 'Interleukin 1-b responses to bacterial toxins and sudden infant death syndrome', FEMS Immunology and Medical Microbiology, 42 139-145 (2004) [C1]
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2004 |
Blackwell CC, Moscovis SM, Gordon AE, Al Madani OM, Hall ST, Gleeson M, et al., 'Ethnicity, infection and sudden infant death syndrome', FEMS Immunology and Medical Microbiology, 42 53-65 (2004) [C1]
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2004 |
Spigelman AD, Burgess BT, Groombridge C, Scott R, 'Genetic testing: a round table conversation', Internal Medicine Journal, 34 587-588 (2004) [C1]
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2004 |
Scott R, Ashton KA, 'Familial breast and bowel cancer: Does it exist?', Hereditary Cancer in Clinical Practice, 2 25-59 (2004) [C1]
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2004 |
Scott R, 'DNA Double Strand Break Repair and its Association with Inherited Predispositions to Breast Cancer', Hereditary Cancer in Clinical Practice, 2 37-43 (2004) [C1]
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2004 |
Gawdis-Wojnarska B, Brzoska M, Flicinski J, Marlicz K, Starzynska T, Scott R, Lubinski J, 'Nuclear Pedigree Criteria for the Identification of Individuals Suspected to be at Risk of an Inherited Predisposition to Gastric Cancer', Hereditary Cancer in Clinical Practice, 2 65-68 (2004) [C1]
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2004 |
Scott R, Crooks R, Rose L, Attia JR, Thakkinstian A, Thomas L, et al., 'Germline Missense Changes in the APC Gene and Their Relationship to Disease', Hereditary Cancer in Clinical Practice, 2 81-91 (2004) [C1]
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2004 |
Liu X, Sinn H-P, Ulmer HU, Scott R, Hamann U, 'Intronic TP53 Germline Sequence Variants Modify the Risk in German Breast/Ovarian Cancer Families', Hereditary Cancer in Clinical Practice, 2 139-145 (2004) [C1]
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2003 |
Meldrum CJ, McPhillips M, Crooks R, Thomas L, Edkins T, Creegan R, et al., 'A comparison between denaturing gradient gel electrophoresis and denaturing high performance liquid chromatography in detecting mutations in genes associated with hereditary non-polyposis colorectal cancer (HNPCC) and the identification of 9 new mutations previously unidentified by DGGE', Hereditary Cancer in Clinical Practice, 1 39-48 (2003) [C1]
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2003 |
Scott RJ, Vajdic CM, Armstrong BK, Ainsworth CJ, Meldrum CJ, Aitken JF, Kricker A, 'BRCA2 mutations in a population-based series of patients with ocular melanoma. (vol 102, pg 188, 2003)', INTERNATIONAL JOURNAL OF CANCER, 105 882-882 (2003)
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2003 |
Scott RJ, Vajdic CM, Armstrong BK, Ainsworth CJ, Meldrum CJ, Aitken JF, Kricker A, 'Erratum: BRCA2 mutations in a population-based series of patients with ocular melanoma (International Journal of Cancer (2003) 102 (188-191))', International Journal of Cancer, 105 882 (2003) |
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2003 |
Górski B, D bniak T, Masojc B, Mierzejewski M, M drek K, Cybulski C, et al., 'Erratum: Germline 657del5 mutation in the NBSI gene in breast cancer patients (International Journal Cancer (2003) 106 (379-381))', International Journal of Cancer, 106 984 (2003)
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2003 |
Gorski B, Debniak T, Mosojc B, Mierzejewski M, Medrek K, Cybulski C, et al., 'Germline 657del5 mutation in the NBS1 gene in breast cancer patients', International Journal of Cancer, 106 379-381 (2003) [C1]
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2003 |
Lubinski W, Kurzawski G, Suchy J, Szych Z, Penkala K, Palacz O, et al., 'Electro-Oculographic and Electroretinographic Studies in HNPCC Gene Mutation Carriers', Ophthalmic Research, 35 281-294 (2003) [C1]
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2003 |
Jakubowska A, Scott R, Menkiszak J, Gronwald J, Byrski T, Huzarski T, et al., 'A high frequency of BRCA2 gene mutations in Polish families with ovarian and stomach cancer', European Journal of Human Genetics, 11 955-958 (2003) [C1]
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2002 |
Scott R, Crooks R, Meldrum C, Thomas L, Smith C, Mowat D, et al., 'Mutation analysis of the STK11/LKB1 gene and clinical characteristics of an Australian series of Peutz-Jeghers syndrome patients', Clinical Genetics, 62 282-287 (2002) [C1]
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2002 |
Scott R, Vajdic C, Armstrong B, Ainsworth C, Meldrum C, Aitken J, Kricker A, 'BRCA2 Mutations in a Population-Based Series of Patients with Ocular Melanoma', International Journal of Cancer, 102 188-191 (2002) [C1]
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2002 |
Niu J, Dorahy DJ, Gu X, Scott R, Draganic B, Ahmed N, Agrez MV, 'Integrin expression in colon cancer cells is regulated by the cytoplasmic domain of the 6 integrin subunit', International Journal of Cancer, 99(4) 529-537 (2002) [C1]
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2002 |
Hamann U, Liu X, Lange S, Ulmer H, Benner A, Scott R, 'Contribution of BRCA2 germline mutations to hereditary breast/ovarian cancer in Germany', Journal of Medical Genetics, 39:e12 1 of 6 (2002) [C1]
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2002 |
Kurzawski G, Safranow K, Suchy J, Chlubek D, Scott R, Lubinski J, 'Mutation analysis of MLH1 and MSH2 genes performed by denaturing high-performance liquid chromatography', Journal of Biochemical and Biophysical Methods, 51 89-100 (2002) [C1]
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2002 |
Ward R, Meldrum C, Williams R, Mokany E, Scott R, Turner J, et al., 'Impact of microsatellite testing and mismatch repair protein expression on the clinical interpretation of genetic testing in hereditary non-polyposis colorectal cancer', Journal of Cancer Research and Clinical Oncology, 128(8) 403-411 (2002) [C1]
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2002 |
Ahmed N, Niu J, Dorahy DJ, Gu X, Andrews S, Meldrum C, et al., 'Direct integrin v 6-ERK binding: implications for tumour growth', Oncogene, 21 1370-1380 (2002) [C1]
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2002 |
Mural RJ, Adams MD, Myers EW, Smith HO, Miklos GLG, Wides R, et al., 'A comparison of whole-genome shotgun-derived mouse chromosome 16 and the human genome', SCIENCE, 296 1661-1671 (2002)
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2002 |
Jukubowska A, Nej K, Huzarski T, Scott R, Lubinski J, 'BRCA2 gene mutations in families with aggregations of breast and stomach cancers', British Journal of Cancer, 87 888-891 (2002) [C1]
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2002 |
Gu X, Niu J, Dorahy D, Scott R, Agrez M, 'Integrin av/B6-associated ERK2 mediates MMP-9 secretion in colon cancer cells', British Journal of Cancer, 87 348-351 (2002) [C1]
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2001 |
Venter JC, Adams MD, Myers EW, Li PW, Mural RJ, Sutton GG, et al., 'The sequence of the human genome', SCIENCE, 291 1304-+ (2001)
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2001 |
Hertz JM, Juncker I, Persson U, Matthijs G, Schmidtke J, Petersen MB, et al., 'Detection of mutations in the COL4A5 gene by SSCP in X-linked Alport syndrome', HUMAN MUTATION, 18 141-148 (2001)
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2001 |
Guldenschuh I, Hurlimann R, Muller A, Ammann R, Mullhaupt B, Zala GF, et al., 'Relationship between APC genotype, polyp distribution, and oral sulindac treatment in the colon and rectum of patients with familial adenomatous polyposis - Reply', DISEASES OF THE COLON & RECTUM, 44 1098-1099 (2001)
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2001 |
Meldrum CJ, Crooks R, Scott RJ, 'D-HPLC detection of APC mutations.', AMERICAN JOURNAL OF HUMAN GENETICS, 69 269-269 (2001)
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Nova |
2001 |
Scott R, McPhillips M, Meldrum C, Fitzgerald P, Adams K, Spigelman A, et al., 'Hereditary non polyposis colorectal cancer in 95 families: differences and similarities between mutation-positive and mutation-negative kindreds', American Journal of Human Genetics, 68 118-127 (2001) [C1]
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Nova |
2001 |
Scott R, 'Reply to Vasen et al', American Journal of Human Genetics, 68 1534-1535 (2001) [C3]
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2001 |
Thompson D, Easton D, Breast Cancer Linkage Consortium Bclc, Scott R, 'Variation in cancer risks, by mutation position, in BRCA2 mutation carriers', American Journal of Human Genetics, 68 410-419 (2001) [C1] |
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2001 |
Scott R, McPhillips M, Meldrum C, Fitzgerald P, Adams K, Spigelman AD, et al., 'Hereditary nonpolyposis colorectal cancer in 95 families: differences and similarities between mutation-positive and mutation-negative kindreds', The American Journal of Human Genetics, 68 118-127 (2001) [C1]
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2001 |
Guldenschuh I, Hurlimann R, Muller A, Ammann R, Mullhaupt B, Dobbie Z, et al., 'Relationship between APC Genotype, Polyp Distribution and Oral Sulindac Treatment in the Colon and Rectum of Patients with Familial Adenomatous Polyposis', Diseases of the Colon and Rectum, 44 1090-1099 (2001) [C1]
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2001 |
Scott R, Meldrum C, Crooks R, Spigelman A, Kirk J, Tucker K, et al., 'Familial adenomatous polyposis: more evidence for disease diversity and genetic heterogeneity', Gut, 48 508-514 (2001) [C1]
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2001 |
Jakubowska A, Gorski B, Kurzawski G, Debniak T, Hadaczek P, Cybulski C, et al., 'Optimization of experimental conditions for RNA-based sequencing of MLH1 and MSH2 genes', Human Mutation, 17 52-60 (2001) [C1]
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2001 |
Jakubowska A, Gorski B, Byrski T, Huzarski T, Gronwald J, Menkiszak J, et al., 'Detection of germline mutations in the BRCA1 gene by RNA-based sequencing', Human Mutation, 18 149-156 (2001) [C1]
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2001 |
Humar B, Muller H, Scott R, 'Cell cycle dependent DNA break increase in ataxia telangiectasia lymphoblasts after radiation exposure', Molecular Pathology, 54 347-350 (2001) [C1]
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2001 |
Connor JR, Milward EA, Moalem S, Sampietro M, Boyer P, Percy ME, et al., 'Is hemochromatosis a risk factor for Alzheimer''s disease?', Journal of Alzheimer''s Disease, 3 471-477 (2001) [C1]
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2001 |
Nasioulas S, Jones I, Stjohn D, Scott R, Forrest S, Gardner R, 'Profuse familial adenomatous polyposis with an APC exon 3 mutation', Familial Cancer, 1 3-7 (2001) [C1]
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2000 |
Scott R, Spigelman AD, 'Tumour site, sex, and survival in colorectal cancer', The Lancet, 356 857 (2000) [C3] |
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2000 |
Ritz M, Lechner-Scott J, Scott R, Fuhr P, Malik N, Erne B, et al., 'Characterisation of autoantibodies to peripheral myelin protein 22 in patients with hereditary and acquired neuropathies', Journal of Neuroimmunology, 104 155-163 (2000) [C1]
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2000 |
Lakhani S, Gusterson B, Jacquemier J, Sloane J, Anderson T, Van De Vijver M, et al., 'The Pathology of Familial Breast Cancer: Histological Features of Cancers in Families Not Attributable to Mutations in BRCA1 or BRCA21', Clinical Cancer Research, 6 782-789 (2000) [C1]
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2000 |
Rosell R, Abad A, 'Tumour site, sex, and survival in colorectal cancer', LANCET, 356 857-857 (2000)
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1999 |
Scott RJ, Sobol HH, 'Prognostic implications of cancer susceptibility genes: Any news?', CHEMOPREVENTION OF CANCER, 151 71-84 (1999)
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1999 |
Heinimann K, Scott RJ, Buerstedde JM, Weber W, Siebold K, Attenhofer M, et al., 'Influence of selection criteria on mutation detection in patients with hereditary nonpolyposis colorectal cancer', Cancer, 85 2512-2518 (1999)
BACKGROUND. Hereditary nonpolyposis colorectal cancer (HNPCC) is linked genetically to mutations in DNA mismatch repair (MMB) genes. Because a deficiency in MMR does not predict a... [more]
BACKGROUND. Hereditary nonpolyposis colorectal cancer (HNPCC) is linked genetically to mutations in DNA mismatch repair (MMB) genes. Because a deficiency in MMR does not predict a specific phenotype, the original selection criteria may be too restrictive in identifying additional families. The current study was performed to determine whether a relaxation of the Amsterdam criteria (AC) could be applied to identify more families associated with DNA MMB. METHODS. Twenty-eight unrelated Swiss families (15 complying with the AC and 13 fulfilling extended criteria [EC] to include other tumors of the HNPCC spectrum as well) were screened for mutations in the MMR genes hMSH2 and hMLH1, using single-stranded conformation polymorphism and direct DNA sequencing. Microsatellite instability (MSI) was determined in 14 families. A comparison was made between the phenotypic characteristics of the mutation positive and mutation negative families. RESULTS. Ten AC families (67%) harbored germline mutations in hMLH1 (6 kindreds) or hMSH2 (4 kindreds). In none of the EC kindreds could an unambiguous disease-causing mutation be identified. Seven of eight AC families were found to display MSI whereas all colorectal carcinomas (CRC) in eight EC kindreds were MSI stable. CRC patients from mutation positive families had an earlier age at diagnosis (44 years vs. 49 years) and appeared to have a better survival (11.1 years vs. 7.7 years). CONCLUSIONS. Extending the AC to include extracolonic tumors of the HNPCC spectrum results in a very low mutation detection rate for hMSH2 and hMLH1. The EC families appear to represent an alternative genetic entity not necessarily related to DNA MMR gene mutations because they do not display MSI.
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1999 |
Heinimann K, Scott RJ, Chappuis P, Weber W, Muller H, Dobbie Z, Hutter P, 'N-acetyltransferase 2 influences cancer prevalence in hMLH1/hMSH2 mutation carriers', CANCER RESEARCH, 59 3038-3040 (1999)
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1998 |
Heinimann K, Mullhaupt B, Weber W, Attenhofer M, Scott RJ, Fried M, et al., 'Phenotypic differences in familial adenomatous polyposis based on APC gene mutation status', GUT, 43 675-679 (1998)
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1998 |
Ford D, Easton DF, Stratton M, Narod S, Goldgar D, Devilee P, et al., 'Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families', AMERICAN JOURNAL OF HUMAN GENETICS, 62 676-689 (1998)
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1998 |
Neuhausen SL, Godwin AK, Gershoni-Baruch R, Schubert E, Garber J, Stoppa-Lyonnet D, et al., 'Haplotype and phenotype analysis of nine recurrent BRCA2 mutations in 111 families: Results of an international study', AMERICAN JOURNAL OF HUMAN GENETICS, 62 1381-1388 (1998)
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1998 |
Lakhani SR, Jacquemier J, Sloane JP, Gusterson BA, Anderson TJ, van de Vijver MJ, et al., 'Multifactorial analysis of differences between sporadic breast cancers and cancers involving BRCA1 and BRCA2 mutations', JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE, 90 1138-1145 (1998)
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1998 |
Maier D, Zhang ZW, Taylor E, Hamou MF, Gratzl O, Van Meir EG, et al., 'Somatic deletion mapping on chromosome 10 and sequence analysis of PTEN/MMAC1 point to the 10q25-26 region as the primary target in low-grade and high-grade gliomas', ONCOGENE, 16 3331-3335 (1998)
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1997 |
Hamann U, Brauch H, Garvin AM, Bastert G, Scott RJ, 'German family study on hereditary breast and/or ovarian cancer: Germline mutation analysis of theBRCA1 gene', Genes, Chromosomes and Cancer, 18 126-132 (1997)
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1997 |
AndreuttiZaugg C, Scott RJ, Iggo R, 'Inhibition of nonsense-mediated messenger RNA decay in clinical samples facilitates detection of human MSH2 mutations with an in vivo fusion protein assay and conventional techniques', CANCER RESEARCH, 57 3288-3293 (1997)
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1997 |
Heinimann K, Muller H, Weber W, Scott RJ, 'Disease expression in Swiss hereditary non-polyposis colorectal cancer (HNPCC) kindreds', INTERNATIONAL JOURNAL OF CANCER, 74 281-285 (1997)
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1997 |
Garvin AM, Attenhofer-Haner M, Scott RJ, 'BRCA1 and BRCA2 mutation analysis in 86 early onset breast/ovarian cancer patients', JOURNAL OF MEDICAL GENETICS, 34 990-995 (1997)
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1997 |
Hamann U, Haner M, Stosiek U, Bastert G, Scott RJ, 'Low frequency of BRCA1 germline mutations in 45 German breast/ovarian cancer families', JOURNAL OF MEDICAL GENETICS, 34 884-888 (1997)
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1997 |
LechnerScott J, Steck AJ, Scott RJ, 'Genetic analyses in neurology', SCHWEIZERISCHE MEDIZINISCHE WOCHENSCHRIFT, 127 1141-1153 (1997)
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1997 |
ShattuckEidens D, Oliphant A, McClure M, McBride C, Gupte J, Rubano T, et al., 'BRCA 1 sequence analysis in women at high risk for susceptibility mutations - Risk factor analysis and implications for genetic testing', JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION, 278 1242-1250 (1997)
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1997 |
Lakhani SR, Easton DF, Stratton MR, StorferIsser A, Anderson TJ, Farid LM, et al., 'Pathology of familial breast cancer: Differences between breast cancers in carriers of BRCA1 or BRCA2 mutations and sporadic cases', LANCET, 349 1505-1510 (1997)
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1997 |
Dobbie Z, Heinimann K, Bishop DT, Muller H, Scott RJ, 'Identification of a modifier gene locus on chromosome 1p35-36 in familial adenomatous polyposis', HUMAN GENETICS, 99 653-657 (1997)
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1997 |
Scott RJ, 'DNA mismatch repair and hereditary nonpolyposis colorectal cancer', ONKOLOGIE, 20 42-47 (1997)
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1997 |
Maier D, Comparone D, Taylor E, Zhang ZW, Gratzl O, Van Meir EG, et al., 'New deletion in low-grade oligodendroglioma at the glioblastoma suppressor locus on chromosome 10q25-26', ONCOGENE, 15 997-1000 (1997)
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1997 |
Humar B, Muller H, Scott RJ, 'Elevated frequency of p53-independent apoptosis after irradiation increases levels of DNA breaks in ataxia telangiectasia lymphoblasts', INTERNATIONAL JOURNAL OF RADIATION BIOLOGY, 72 257-269 (1997)
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1997 |
Garvin AM, Eppenberger U, Muller H, EppenbergerCastori S, Scott RJ, 'BRCA1 mutations found in archived early onset breast tumours', EUROPEAN JOURNAL OF CANCER, 33 683-686 (1997)
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1997 |
Scott RJ, Taeschner W, Heinimann K, Muller H, Dobbie Z, Morgenthaler S, et al., 'Association of extracolonic manifestations of familial adenomatous polyposis with acetylation phenotype in a large FAP kindred', EUROPEAN JOURNAL OF HUMAN GENETICS, 5 43-49 (1997)
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1997 |
Hamann U, Brauch H, Garvin AM, Bastert G, Scott RJ, 'German family study on hereditary breast and/or ovarian cancer: Germline mutation analysis of the BRCAI gene', GENES CHROMOSOMES & CANCER, 18 126-132 (1997)
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1997 |
Scott RJ, 'Abteilung humangenetik, forschungsdepartement, kantonsspital basel, schweiz', Oncology Research and Treatment, 20 42-47 (1997)
Hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal dominantly inherited disorder which is characterized by the absence of a premalignant phenotype. Until recently, ... [more]
Hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal dominantly inherited disorder which is characterized by the absence of a premalignant phenotype. Until recently, the only method to identify persons with a predisposition to develop colorectal cancer was by rigorous anamnestic questioning of their family history. The recent discovery that mutations in genes associated with mismatch repair predispose persons to the development of HNPCC has on the one hand provided a more accurate alternative to pedigree analysis but on the other is accompanied by special difficulties with respect to genetic counselling. This review focuses on what is meant by HNPCC, the current knowledge of mismatch repair, mismatch repair gene mutations, their resulting genetic phenotype, its implication in tumour development and screening alternatives for gene carriers. © 1996 S. Karger GmbH, Freiburg.
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1996 |
Merlo A, Rochlitz C, Scott R, 'Survival of patients with Turcot's syndrome and glioblastoma', NEW ENGLAND JOURNAL OF MEDICINE, 334 736-737 (1996)
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1996 |
Scott RJ, 'Novel germline APC gene mutation in a large familial adenomatous polyposis kindred displaying variable phenotypes (vol 36, pg 731, 1995)', GUT, 38 794-794 (1996)
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1996 |
Dobbie Z, Spycher M, Mary JL, Haner M, Guldenschuh I, Hurliman R, et al., 'Correlation between the development of extracolonic manifestations in FAP patients and mutations beyond codon 1403 in the APC gene', JOURNAL OF MEDICAL GENETICS, 33 274-280 (1996)
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1996 |
Hutter P, Couturier A, Scott RJ, Alday P, DelozierBlanchet C, Cachat F, et al., 'Complex genetic predisposition to cancer in an extended HNPCC family with an ancestral hMLH1 mutation', JOURNAL OF MEDICAL GENETICS, 33 636-640 (1996)
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1996 |
Garvin AM, Spycher M, Haner M, Torhorst J, Muller H, Herrmann R, et al., 'BRCA1 mutations in a selected series of breast ovarian cancer patients', JOURNAL OF MEDICAL GENETICS, 33 721-725 (1996)
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1996 |
Garvin AM, Mueller H, EppenbergerCastori S, Eppenberger URS, Scott RJ, 'Informed consent and BRCA1 mutation detection in archived breast tumour specimens', LANCET, 347 1189-1189 (1996)
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1996 |
Dobbie Z, Muller H, Scott RJ, 'Secretory phospholipase A(2) does not appear to be associated with phenotypic variation in familial adenomatous polyposis', HUMAN GENETICS, 98 386-390 (1996)
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1996 |
vanderLuijt RB, Khan PM, Vasen HFA, Breukel C, Tops CMJ, Scott RJ, Fodde R, 'Germline mutations in the 3' part of APC exon 15 do not result in truncated proteins and are associated with attenuated adenomatous polyposis coli', HUMAN GENETICS, 98 727-734 (1996)
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1996 |
Scott RJ, Froggatt NJ, Trembath RC, Evans DGR, Hodgson SV, Maher ER, 'Familial infiltrative fibromatosis (desmoid tumours) (MIM135290) caused by a recurrent 3' APC gene mutation', HUMAN MOLECULAR GENETICS, 5 1921-1924 (1996)
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1996 |
Garvin AM, Mueller H, Eppenberger-Castori S, Eppenberger URS, Scott RJ, 'Informed consent and BRCA1 mutation detection in archived breast tumour specimens [10]', Lancet, 347 189 (1996) |
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1995 |
BUERSTEDDE JM, ALDAY P, TORHORST J, WEBER W, MULLER H, SCOTT R, 'DETECTION OF NEW MUTATIONS IN 6 OUT OF 10 SWISS HNPCC FAMILIES BY GENOMIC SEQUENCING OF THE HMSH2 AND HMLH1 GENES', JOURNAL OF MEDICAL GENETICS, 32 909-912 (1995)
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1995 |
SCOTT RJ, VANDERLUIJT R, SPYCHER M, MARY JL, MULLER A, HOPPELER T, et al., 'NOVEL GERMLINE APC GENE MUTATION IN A LARGE FAMILIAL ADENOMATOUS POLYPOSIS KINDRED DISPLAYING VARIABLE PHENOTYPES', GUT, 36 731-736 (1995)
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1995 |
MULLER H, SCOTT RJ, 'TUMOR-SUPPRESSOR GENE-MUTATIONS IN THE GERM-LINE - THEIR OCCURRENCE IN FAMILIAL AND SPORADIC CANCER', SCHWEIZERISCHE MEDIZINISCHE WOCHENSCHRIFT, 125 1445-1454 (1995)
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1995 |
Müller H, Scott RJ, 'Familial colorectal and breast carcinoma--genetic counseling and presymptomatic diagnosis', Therapeutische Umschau. Revue thérapeutique, 52 826-834 (1995)
Several types of hereditary cancer can be prevented from progressing to advanced stages by regular surveillance of the person at risk and hence by the early treatment of a develop... [more]
Several types of hereditary cancer can be prevented from progressing to advanced stages by regular surveillance of the person at risk and hence by the early treatment of a developing neoplasia. Genetic counselling of such patients and their relatives is therefore an important task whose value often remains unrecognized. This is especially true for the common forms of hereditary cancer such as breast and colorectal cancer, which aggregate in up to 5% of all patients according to the rules of autosomal-dominant inheritance. Preventive measures are particularly promising in the case of familial cancer because persons at risk are motivated to seek medical help. Genetic counselling is a multifaceted process and involves more than an accurate diagnosis and risk estimate. The counseled patient expects and deserves an open and reasonable answer to his questions about the implications of his/her cancer predisposition or his family history. Accurate diagnosis of the underlying susceptibility is the cornerstone of genetic counselling because most cancers seem to have multiple causes. Different genes located on different chromosomes can independently give rise to the same malignancy. Besides heterogeneity, presymptomatic testing for inherited susceptibilities to cancer raises many issues including therapy, access, intense anxiety, and discrimination.
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1995 |
Lechner-Scott JS, Scott RJ, Steck AJ, Kappos L, 'Hereditary motor sensory neuropathies. Clinical and molecular genetic aspects', Schweizer Archiv fur Neurologie und Psychiatrie, 146 (1995)
Hereditary motor sensory neuropathies are a heterogeneous group of inherited diseases of the peripheral nerves. In this review the clinical and genetic differences between the sub... [more]
Hereditary motor sensory neuropathies are a heterogeneous group of inherited diseases of the peripheral nerves. In this review the clinical and genetic differences between the sub-groups of this disease will be discussed. Since the discovery of a 1.5 mb duplication on chromosome 17 p11.2-12 in most patients with a hereditary motor sensory neuropathy and a variety of different mutations on chromosomes 1 and X in other patients with a similar disease profile, Dycks' clinical classification needs to be re-evaluated. In this review Dycks' taxonomy of hereditary neuropathies will be compared to a new genetic classification and a relevant diagnostic procedure proposed when a hereditary neuropathy is suspected.
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1994 |
MULLER H, SCOTT R, WEBER W, MEIER R, 'COLORECTAL-CANCER - LESSONS FOR GENETIC-COUNSELING AND CARE FOR FAMILIES', CLINICAL GENETICS, 46 106-114 (1994)
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1994 |
REY JP, SCOTT R, MULLER H, 'APOPTOSIS IS NOT INVOLVED IN THE HYPERSENSITIVITY OF FANCONI-ANEMIA CELLS TO MITOMYCIN-C', CANCER GENETICS AND CYTOGENETICS, 75 67-71 (1994)
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1994 |
VERMEULEN W, SCOTT RJ, RODGERS S, MULLER HJ, COLE J, ARLETT CF, et al., 'CLINICAL HETEROGENEITY WITHIN XERODERMA-PIGMENTOSUM ASSOCIATED WITH MUTATIONS IN THE DNA-REPAIR AND TRANSCRIPTION GENE ERCC3', AMERICAN JOURNAL OF HUMAN GENETICS, 54 191-200 (1994)
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1994 |
MULLER H, SCOTT RJ, 'HOW COMMON IS HEREDITARY CANCER', ANNALS OF MEDICINE, 26 173-175 (1994)
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1994 |
DOBBIE Z, SPYCHER M, HURLIMAN R, AMMANN R, AMMANN T, ROTH J, et al., 'MUTATIONAL ANALYSIS OF THE FIRST 14 EXONS OF THE ADENOMATOUS POLYPOSIS-COLI (APC) GENE', EUROPEAN JOURNAL OF CANCER, 30A 1709-1713 (1994)
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1994 |
MARY JL, BISHOP T, KOLODNER R, LIPFORD JR, KANE M, WEBER W, et al., 'MUTATIONAL ANALYSIS OF THE HMSH2 GENE REVEALS A 3-BASE-PAIR DELETION IN A FAMILY PREDISPOSED TO COLORECTAL-CANCER DEVELOPMENT', HUMAN MOLECULAR GENETICS, 3 2067-2069 (1994)
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1993 |
REY JP, SCOTT R, MULLER H, 'INDUCTION AND REMOVAL OF INTERSTRAND CROSS-LINKS IN THE RIBOSOMAL-RNA GENES OF LYMPHOBLASTOID CELL-LINES FROM PATIENTS WITH FANCONI-ANEMIA', MUTATION RESEARCH, 289 171-180 (1993)
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1993 |
SCOTT RJ, KRUMMENACHER F, MARY JL, WEBER W, SPYCHER M, MULLER H, 'INHERITABLE P53 MUTATION IN A PATIENT WITH MULTIPLE CANCER AND ITS SIGNIFICATION FOR GENETIC-COUNSELING', SCHWEIZERISCHE MEDIZINISCHE WOCHENSCHRIFT, 123 1287-1292 (1993)
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1993 |
SCOTT RJ, ITIN P, KLEIJER WJ, KOLB K, ARLETT C, MULLER H, 'XERODERMA-PIGMENTOSUM COCKAYNE-SYNDROME COMPLEX IN 2 PATIENTS - ABSENCE OF SKIN TUMORS DESPITE SEVERE DEFICIENCY OF DNA EXCISION-REPAIR', JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY, 29 883-889 (1993)
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1993 |
SCOTT RJ, MULLER H, 'FAMILIAL AND GENETIC-ASPECTS OF COLORECTAL CARCINOGENESIS', EUROPEAN JOURNAL OF CANCER, 29A 2163-2167 (1993)
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1992 |
SCOTT R, 'IL-2 APPROVAL RECOMMENDED BY FDA PANEL', JOURNAL OF THE NATIONAL CANCER INSTITUTE, 84 226-227 (1992)
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1992 |
SCOTT R, 'DERMATOLOGISTS WARN NATION OF INCREASED SKIN-CANCER RISK', JOURNAL OF THE NATIONAL CANCER INSTITUTE, 84 1696-1696 (1992)
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1992 |
OU CY, CIESIELSKI CA, MYERS G, BANDEA CI, LUO CC, KORBER BTM, et al., 'MOLECULAR EPIDEMIOLOGY OF HIV TRANSMISSION IN A DENTAL PRACTICE', SCIENCE, 256 1165-1171 (1992)
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1992 |
MULLER H, SCOTT R, 'HEREDITARY CONDITIONS IN WHICH THE LOSS OF HETEROZYGOSITY MAY BE IMPORTANT', MUTATION RESEARCH, 284 15-24 (1992)
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1991 |
SCOTT RJ, HALL PA, HALDANE JS, VANNOORDEN S, PRICE Y, LANE DP, WRIGHT NA, 'A COMPARISON OF IMMUNOHISTOCHEMICAL MARKERS OF CELL-PROLIFERATION WITH EXPERIMENTALLY DETERMINED GROWTH FRACTION', JOURNAL OF PATHOLOGY, 165 173-178 (1991)
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1991 |
SCOTT R, 'COMMISSION URGES STRONGER LEADERSHIP AGAINST AIDS', JOURNAL OF THE NATIONAL CANCER INSTITUTE, 83 1449-1449 (1991)
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1990 |
SCOTT RJ, HAMMONS KV, HUNT JM, 'CHANGES IN THE EXPRESSION OF CLASS-I MAJOR HISTOCOMPATIBILITY COMPLEX ANTIGEN RNA INDUCED BY INTERFERON IN RAT HEPATOMA-CELLS', CANCER LETTERS, 50 209-213 (1990)
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1989 |
SCOTT RJ, CHAKRABORTY S, SELL S, HUNT JM, DUNSFORD HA, 'CHANGE IN THE PLOIDY STATE OF RAT-LIVER CELLS DURING CHEMICAL HEPATOCARCINOGENESIS AND ITS RELATIONSHIP TO THE INCREASED EXPRESSION OF ALPHA-FETOPROTEIN', CANCER RESEARCH, 49 6085-6090 (1989)
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1989 |
COCKBURN J, HENNRIKUS D, SCOTT R, SANSONFISHER R, 'ADOLESCENT USE OF SUN-PROTECTION MEASURES', MEDICAL JOURNAL OF AUSTRALIA, 151 136-140 (1989)
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1988 |
SCOTT RJ, ENGLISH V, NOGUCHI T, TANAKA T, YEOH GCT, 'PYRUVATE-KINASE ISOENZYME TRANSITIONS IN CULTURES OF FETAL-RAT HEPATOCYTES', CELL DIFFERENTIATION AND DEVELOPMENT, 25 109-118 (1988)
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1987 |
GILLETTE EL, MCCHESNEY SL, DEWHIRST MW, SCOTT RJ, 'RESPONSE OF CANINE ORAL CARCINOMAS TO HEAT AND RADIATION', INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS, 13 1861-1867 (1987)
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1985 |
MACY DW, MACY CA, SCOTT RJ, GILLETTE EL, SPEER JF, 'PHYSIOLOGICAL-STUDIES OF WHOLE-BODY HYPERTHERMIA OF DOGS', CANCER RESEARCH, 45 2769-2773 (1985)
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1984 |
SCOTT R, YEOH GCT, 'A REQUIREMENT FOR DNA-SYNTHESIS IN FETAL HEPATOCYTE DIFFERENTIATION - EFFECT OF CYTOSINE-ARABINOSIDE ON THE APPEARANCE OF THE LIVER ISOENZYME OF PYRUVATE-KINASE', DIFFERENTIATION, 28 49-52 (1984)
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1984 |
SCOTT R, YEOH GCT, 'EFFECT OF 5-BROMODEOXYURIDINE ON THE APPEARANCE OF THE LIVER ISOENZYME OF PYRUVATE-KINASE', BIOCHEMICAL JOURNAL, 220 865-868 (1984)
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1984 |
GREENWOOD MH, COETZEE EFC, FORD BM, GILL P, HOOPER WL, MATTHEWS SCW, et al., 'THE MICROBIOLOGY OF SELECTED RETAIL FOOD-PRODUCTS WITH AN EVALUATION OF VIABLE COUNTING METHODS', JOURNAL OF HYGIENE, 92 67-77 (1984)
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1984 |
Scott RJ, Yeoh GCT, 'Appearance of the liver form of pyruvate kinase in differentiating cultured foetal hepatocytes', Differentiation, 25 64-69 (1984)
From about the 16th day of gestation three forms of pyruvate kinase are present in foetal rat liver (L, R, and M2). Hepatocytes isolated from 15-day-old foetuses do not possess th... [more]
From about the 16th day of gestation three forms of pyruvate kinase are present in foetal rat liver (L, R, and M2). Hepatocytes isolated from 15-day-old foetuses do not possess the liver form of pyruvate kinase, but after three days in culture this enzyme can be detected. No effect on the appearance of the enzyme could be seen by administration of insulin and fructose. Hepatocytes isolated from 19-day-old foetuses exhibit three forms of the enzyme (L, R, and M2) on day 1 of culture but thereafter only two forms are detectable (L and M2). A decrease in activity of the L form is observed. This could be retarded by administration of insulin and fructose. © 1984, International Society of Differentiation. All rights reserved.
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1983 |
SCOTT RJ, YEOH GCT, 'APPEARANCE OF THE LIVER FORM OF PYRUVATE-KINASE IN DIFFERENTIATING CULTURED FETAL HEPATOCYTES', DIFFERENTIATION, 25 64-69 (1983)
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1983 |
RUCKER NC, LUMB WV, SCOTT RJ, 'COMBINED PHARMACOLOGIC AND SURGICAL TREATMENTS FOR ACUTE SPINAL-CORD TRAUMA', ANNALS OF THE NEW YORK ACADEMY OF SCIENCES, 411 191-199 (1983)
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Scott RJ, Gastony GJ, Weatherford JW, Nakazato T, 'Characterization of four members of the alpha-tubulin gene family in
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THRALL DE, PAGE RL, DEWHIRST MW, MACY DW, MCLEOD DA, SCOTT RJ, et al., 'WHOLE-BODY HYPERTHERMIA IN DOGS USING A RADIANT HEATING DEVICE - EFFECT OF SURFACE COOLING ON TEMPERATURE UNIFORMITY', INTERNATIONAL JOURNAL OF HYPERTHERMIA, 5 137-143
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GILLETTE SM, DAWSON CA, SCOTT RJ, RICKABY DA, POWERS BE, JOHNSTON MR, et al., 'WHOLE-BODY HYPERTHERMIA COMBINED WITH HYPERFRACTIONATED IRRADIATION OF THE THORAX IN DOG - ACUTE PHYSIOLOGICAL-RESPONSE', INTERNATIONAL JOURNAL OF HYPERTHERMIA, 9 369-382
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VUJASKOVIC Z, GILLETTE SM, POWERS BE, LARUE SM, GILLETTE EL, BORAK TB, et al., 'EFFECTS OF INTRAOPERATIVE HYPERTHERMIA ON PERIPHERAL-NERVES - NEUROLOGICAL AND ELECTROPHYSIOLOGICAL STUDIES', INTERNATIONAL JOURNAL OF HYPERTHERMIA, 10 41-49
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VUJASKOVIC Z, GILLETTE SM, POWERS BE, GILLETTE EL, SCOTT RJ, WHALEN RL, et al., 'EFFECTS OF INTRAOPERATIVE HYPERTHERMIA ON CANINE SCIATIC-NERVE - HISTOPATHOLOGIC AND MORPHOMETRIC STUDIES', INTERNATIONAL JOURNAL OF HYPERTHERMIA, 10 845-855
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