|2015||RannikmÃ¤e K, Davies G, Thomson PA, Bevan S, Devan WJ, Falcone GJ, et al., 'Common variation in COL4A1/COL4A2 is associated with sporadic cerebral small vessel disease', Neurology, 84 918-926 (2015)|
Objectives: We hypothesized that common variants in the collagen genes COL4A1/COL4A2 are associated with sporadic forms of cerebral small vessel disease. Methods: We conducted meta-analyses of existing genotype data among individuals of European ancestry to determine associations of 1,070 common single nucleotide polymorphisms (SNPs) in the COL4A1/COL4A2 genomic region with the following: intracerebral hemorrhage and its subtypes (deep, lobar) (1,545 cases, 1,485 controls); ischemic stroke and its subtypes (cardioembolic, large vessel disease, lacunar) (12,389 cases, 62,004 controls); and white matter hyperintensities (2,733 individuals with ischemic stroke and 9,361 from population-based cohorts with brain MRI data). We calculated a statistical significance threshold that accounted for multiple testing and linkage disequilibrium between SNPs (p < 0.000084). Results: Three intronic SNPs in COL4A2 were significantly associated with deep intracerebral hemorrhage (lead SNP odds ratio [OR] 1.29, 95% confidence interval [CI] 1.14-1.46, p = 0.00003; r2 > 0.9 between SNPs). Although SNPs associated with deep intracerebral hemorrhage did not reach our significance threshold for association with lacunar ischemic stroke (lead SNP OR 1.10, 95% CI 1.03-1.18, p = 0.0073), and with white matter hyperintensity volume in symptomatic ischemic stroke patients (lead SNP OR 1.07, 95% CI 1.01-1.13, p = 0.016), the direction of association was the same. There was no convincing evidence of association with white matter hyperintensities in population-based studies or with non-small vessel disease cerebrovascular phenotypes. Conclusions: Our results indicate an association between common variation in the COL4A2 gene and symptomatic small vessel disease, particularly deep intracerebral hemorrhage. These findings merit replication studies, including in ethnic groups of non-European ancestry.
|2015||Sapkota Y, Low S-K, Attia J, Gordon SD, Henders AK, Holliday EG, et al., 'Association between endometriosis and the interleukin 1A (ILIA) locus', HUMAN REPRODUCTION, 30 239-248 (2015)|
|2015||Shungin D, Winkler TW, Croteau-Chonka DC, Ferreira T, Locke AE, MÃ¤gi R, et al., 'New genetic loci link adipose and insulin biology to body fat distribution', Nature, 518 187-197 (2015)|
Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 Ã 10-8). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms.
|2015||Battey TWK, Valant V, Kassis SB, Kourkoulis C, Lee C, Anderson CD, et al., 'Recommendations from the international stroke genetics consortium, part 2: Biological sample collection and storage', Stroke, 46 285-290 (2015)|
|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)|
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 55Â¿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.
|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.', Biol Psychiatry, (2015)|
|2015||Painter JN, O'Mara TA, Batra J, Cheng T, Lose FA, Dennis J, et al., 'Fine-mapping of the HNF1B multicancer locus identifies candidate variants that mediate endometrial cancer risk', HUMAN MOLECULAR GENETICS, 24 1478-1492 (2015) [C1]|
|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=53949).', Mol Psychiatry, 20 183-192 (2015)|
|2015||Locke AE, Kahali B, Berndt SI, Justice AE, Pers TH, Day FR, et al., 'Genetic studies of body mass index yield new insights for obesity biology.', Nature, 518 197-206 (2015)|
|2015||Holliday EG, Traylor M, Malik R, Bevan S, Falcone G, Hopewell JC, et al., 'Genetic overlap between diagnostic subtypes of ischemic stroke.', Stroke, 46 615-619 (2015)|
|2015||Gorski M, Tin A, Garnaas M, McMahon GM, Chu AY, Tayo BO, et al., 'Genome-wide association study of kidney function decline in individuals of European descent', KIDNEY INTERNATIONAL, 87 1017-1029 (2015) [C1]|
|2015||Malik R, Freilinger T, Winsvold BS, Anttila V, Vander Heiden J, Traylor M, et al., 'Shared genetic basis for migraine and ischemic stroke', Neurology, 84 2132-2145 (2015)|
Objective: To quantify genetic overlap between migraine and ischemic stroke (IS) with respect to common genetic variation. Methods: We applied 4 different approaches to large-scale meta-analyses of genome-wide data on migraine (23,285 cases and 95,425 controls) and IS (12,389 cases and 62,004 controls). First, we queried known genome-wide significant loci for both disorders, looking for potential overlap of signals. We then analyzed the overall shared genetic load using polygenic scores and estimated the genetic correlation between disease subtypes using data derived from these models. We further interrogated genomic regions of shared risk using analysis of covariance patterns between the 2 phenotypes using cross-phenotype spatial mapping. Results: We found substantial genetic overlap between migraine and IS using all 4 approaches. Migraine without aura (MO) showed much stronger overlap with IS and its subtypes than migraine with aura (MA). The strongest overlap existed between MO and large artery stroke (LAS; p 6.4 Ã 10-28 for the LAS polygenic score in MO) and between MO and cardioembolic stroke (CE; p 2.7 Ã 10-20 for the CE score in MO). Conclusions: Our findings indicate shared genetic susceptibility to migraine and IS, with a particularly strong overlap between MO and both LAS and CE pointing towards shared mechanisms. Our observations on MA are consistent with a limited role of common genetic variants in this subtype.
|2015||Gorski M, Tin A, Garnaas M, McMahon GM, Chu AY, Tayo BO, et al., 'Genome-wide association study of kidney function decline in individuals of European descent.', Kidney international, 87 1017-1029 (2015) [C1]|
|2015||Achterberg S, Kappelle LJ, De Bakker PIW, Traylor M, Algra A, Van Der Graaf Y, et al., 'No additional prognostic value of genetic information in the prediction of vascular events after cerebral ischemia of arterial origin: The PROMISe study', PLoS ONE, 10 (2015)|
Background: Patients who have suffered from cerebral ischemia have a high risk of recurrent vascular events. Predictive models based on classical risk factors typically have limited prognostic value. Given that cerebral ischemia has a heritable component, genetic information might improve performance of these risk models. Our aim was to develop and compare two models: one containing traditional vascular risk factors, the other also including genetic information. Methods and Results: We studied 1020 patients with cerebral ischemia and genotyped them with the Illumina Immunochip. Median follow-up time was 6.5 years; the annual incidence of new ischemic events (primary outcome, n=198) was 3.0%. The prognostic model based on classical vascular risk factors had an area under the receiver operating characteristics curve (AUC-ROC) of 0.65 (95% confidence interval 0.61-0.69). When we added a genetic risk score based on prioritized SNPs from a genome-wide association study of ischemic stroke (using summary statistics from the METASTROKE study which included 12389 cases and 62004 controls), the AUC-ROC remained the same. Similar results were found for the secondary outcome ischemic stroke. Conclusions: We found no additional value of genetic information in a prognostic model for the risk of ischemic events in patients with cerebral ischemia of arterial origin. This is consistent with a complex, polygenic architecture, where many genes of weak effect likely act in concert to influence the heritable risk of an individual to develop (recurrent) vascular events. At present, genetic information cannot help clinicians to distinguish patients at high risk for recurrent vascular events.
|2015||Denham JW, Steigler A, Joseph D, Lamb DS, Spry NA, Duchesne G, et al., 'Radiation dose escalation or longer androgen suppression for locally advanced prostate cancer? Data from the TROG 03.04 RADAR trial.', Radiother Oncol, (2015)|
|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, (2015)|
|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.', Mol Hum Reprod, 21 594-602 (2015)|
|2015||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.', Mol Psychiatry, (2015)|
|2014||Oldmeadow C, Mossman D, Evans TJ, 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]|
|2014||Springelkamp H, HÃ¶hn R, Mishra A, Hysi PG, Khor C-C, 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 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.
|2014||Traylor M, MÃ¤kelÃ¤ KM, Kilarski LL, Holliday EG, Devan WJ, Nalls MA, et al., 'A novel MMP12 locus is associated with large artery atherosclerotic stroke using a genome-wide age-at-onset informed approach.', PLoS Genet, 10 e1004469 (2014) [C1]|
|2014||Evans TJ, 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]|
|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]|
|2014||Kilarski LL, Achterberg S, Devan WJ, Traylor M, Malik R, Lindgren A, et al., 'Meta-analysis in more than 17,900 cases of ischemic stroke reveals a novel association at 12q24.12', NEUROLOGY, 83 678-685 (2014) [C1]|
|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]|
|2014||Malik R, Bevan S, Nalls MA, Holliday EG, Devan WJ, Cheng Y-C, et al., 'Multilocus genetic risk score associates with ischemic stroke in case-control and prospective cohort studies', Stroke, 45 394-402 (2014) [C1]|
Background and Purpose - Genome-wide association studies have revealed multiple common variants associated with known risk factors for ischemic stroke (IS). However, their aggregate effect on risk is uncertain. We aimed to generate a multilocus genetic risk score (GRS) for IS based on genome-wide association studies data from clinical-based samples and to establish its external validity in prospective population-based cohorts. Methods - Three thousand five hundred forty-eight clinic-based IS cases and 6399 controls from the Wellcome Trust Case Control Consortium 2 were used for derivation of the GRS. Subjects from the METASTROKE consortium served as a replication sample. The validation sample consisted of 22 751 participants from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium. We selected variants that had reached genome-wide significance in previous association studies on established risk factors for IS. Results - A combined GRS for atrial fibrillation, coronary artery disease, hypertension, and systolic blood pressure significantly associated with IS both in the case-control samples and in the prospective population-based studies. Subjects in the top quintile of the combined GRS had >2-fold increased risk of IS compared with subjects in the lowest quintile. Addition of the combined GRS to a simple model based on sex significantly improved the prediction of IS in the combined clinic-based samples but not in the population-based studies, and there was no significant improvement in net reclassification. Conclusions - A multilocus GRS based on common variants for established cardiovascular risk factors was significantly associated with IS both in clinic-based samples and in the general population. However, the improvement in clinical risk prediction was found to be small. Â© 2014 American Heart Association, Inc.
|2014||Cotlarciuc I, Malik R, Holliday EG, Ahmadi KR, ParÃ© G, Psaty BM, et al., 'Effect of genetic variants associated with plasma homocysteine levels on stroke risk', Stroke, 45 1920-1924 (2014) [C1]|
BACKGROUND AND PURPOSE - : Elevated total plasma homocysteine (tHcy) levels are known to be associated with increased risk of ischemic stroke (IS). Given that both tHcy and IS are heritable traits, we investigated a potential genetic relationship between homocysteine levels and stroke risk by assessing 18 polymorphisms previously associated with tHcy levels for their association with IS and its subtypes. METHODS - : Previous meta-analysis results from an international stroke collaborative network, METASTROKE, were used to assess association of the 18 tHcy-associated single-nucleotide polymorphisms (SNPs) in 12 389 IS cases and 62 004 controls. We also investigated the associations in regions located within 50 kb from the 18 tHcy-related SNPs and the association of a genetic risk score, including the 18 SNPs. RESULTS - : One SNP located in the RASIP1 gene and a cluster of 3 SNPs located at and near SLC17A3 were significantly associated with IS (P<0.0003) after correcting for multiple testing. For stroke subtypes, the sentinel SNP located upstream of MUT was significantly associated with small-vessel disease (P=0.0022), whereas 1 SNP located in MTHFR was significantly associated with large-vessel disease (P=0.00019). A genetic risk score, including the 18 SNPs, did not show significant association with IS or its subtypes. CONCLUSIONS - : This study found several potential associations with IS and its subtypes: An association of an MUT variant with small-vessel disease, an MTHFR variant with large-vessel disease, and associations of RASIP1 and SLC17A3 variants with overall IS. Â© 2014 American Heart Association, Inc.
|2014||Wang JJ, Buitendijk GHS, Rochtchina E, Lee KE, Klein BEK, Van Duijn CM, et al., 'Genetic susceptibility, dietary antioxidants, and long-term incidence of age-related macular degeneration in two populations', Ophthalmology, 121 667-675 (2014) [C1]|
Objective To examine effect modification between genetic susceptibility to age-related macular degeneration (AMD) and dietary antioxidant or fish consumption on AMD risk. Design Pooled data analysis of population-based cohorts. Participants Participants from the Blue Mountains Eye Study (BMES) and Rotterdam Study (RS). Methods Dietary intakes of antioxidants (lutein/zeaxanthin [LZ], Ã-carotene, and vitamin C), long-chain omega-3 polyunsaturated fatty acids, and zinc were estimated from food frequency questionnaires. The AMD genetic risk was classified according to the number of risk alleles of CFH (rs1061170) or ARMS2 (rs10490924) as low (no or 1 risk allele) or high (=2 risk alleles). Interactions between dietary intake and genetic risk levels were assessed. Associations between dietary intake and AMD risk were assessed comparing the highest with the 2 lower intake tertiles by genetic risk subgroups using discrete logistic regression, conducted in each study separately and then using pooled data. Participants without AMD lesions at any visit were controls. We adjusted for age and sex in analyses of each cohort sample and for smoking status and study site in pooled-data analyses. Main Outcome Measures All 15-year incident late AMD cases were confirmed by chief investigators of the Beaver Dam Eye Study, BMES, and RS. Intergrader reproducibility was assessed in an early AMD subsample, with 86.4% agreement between BMES and RS graders, allowing for a 1-step difference on a 5-step AMD severity scale. Results In pooled data analyses, we found significant interaction between AMD genetic risk status and LZ intake (P = 0.0009) but nonsignificant interactions between genetic risk status and weekly fish consumption (P = 0.05) for risk of any AMD. Among participants with high genetic risk, the highest intake tertile of LZ was associated with a >20% reduced risk of early AMD, and weekly consumption of fish was associated with a 40% reduced risk of late AMD. No similar association was evident among participants with low genetic risk. No interaction was detected between Ã-carotene or vitamin C and genetic risk status. Conclusions Protection against AMD from greater LZ and fish consumption in persons with high genetic risk based on 2 major AMD genes raises the possibility of personalized preventive interventions. Â©2014 by the American Academy of Ophthalmology.
|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]|
|2014||Moir-Meyer GL, Pearson JF, Lose F, The ANECSG, Scott RJ, McEvoy M, et al., 'Rare germline copy number deletions of likely functional importance are implicated in endometrial cancer predisposition', Human Genetics, (2014)|
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 Ã 10-10), CpG islands (P = 1 Ã 10-7) and sno/miRNAs regions (P = 3 Ã 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.
|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]|
|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]|
|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 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.
|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) [C1]|
|2014||Kilarski LL, Achterberg S, Devan WJ, Traylor M, Malik R, Lindgren A, Pare G, 'Meta-analysis in more than 17,900 cases of ischemic stroke reveals a novel association at 12q24.12', Neurology, 83 678-685 (2014) [C1]|
Results: In an overall analysis of 17,970 cases of ischemic stroke and 70,764 controls, we identified a novel association on chromosome 12q24 (rs10744777, odds ratio [OR] 1.10 [1.07-1.13], p 5 7.12 3 10-11) with ischemic stroke. The association was with all ischemic stroke rather than an individual stroke subtype, with similar effect sizes seen in different stroke subtypes. There was no association with intracerebral hemorrhage (OR 1.03 [0.90-1.17], p 5 0.695).
|2014||Ek WE, Reznichenko A, Ripke S, Niesler B, Zucchelli M, Rivera NV, et al., 'Exploring the genetics of irritable bowel syndrome: a GWA study in the general population and replication in multinational case-control cohorts.', Gut, (2014)|
|2013||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, (2013)|
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 Ã 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 Ã 10-10) and replication cohorts (p = 5.65 Ã 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 Ã 10-8, and rs6813517 [SPOCK3], p = 2.58 Ã 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.
|2013||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]|
|2013||Adib-Samii P, Rost N, Traylor M, Devan W, Biffi A, Lanfranconi S, et al., '17q25 Locus is associated with white matter hyperintensity volume in ischemic stroke, but not with lacunar stroke status', Stroke, 44 1609-1615 (2013) [C1]|
|2013||Buitendijk GHS, Rochtchina E, Myers C, Van Duijn CM, Lee KE, Klein BEK, et al., 'Prediction of age-related macular degeneration in the general population: The three continent AMD consortium', Ophthalmology, 120 2644-2655 (2013) [C1]|
|2013||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]|
|2013||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]|
|2013||Parsa A, Fuchsberger C, KÃ¶ttgen A, O'Seaghdha CM, Pattaro C, De Andrade M, et al., 'Common variants in mendelian kidney disease genes and their association with renal function', Journal of the American Society of Nephrology, 24 2105-2117 (2013) [C1]|
Many common genetic variants identified by genome-wide association studies for complex traitsmap to genes previously linked to rare inherited Mendelian disorders. A systematic analysis of common single-nucleotide polymorphisms (SNPs) in genes responsible for Mendelian diseases with kidney phenotypes has not been performed. We thus developed a comprehensive database of genes for Mendelian kidney conditions and evaluated the association between common genetic variants within these genes and kidney function in the general population. Using the Online Mendelian Inheritance in Man database, we identified 731 unique disease entries related to specific renal search terms and confirmed a kidney phenotype in 218 of these entries, corresponding to mutations in 258 genes. We interrogated common SNPs (minor allele frequency >5%) within these genes for association with the estimated GFR in 74,354 European-ancestry participants from the CKDGen Consortium. However, the top four candidate SNPs (rs6433115 at LRP2, rs1050700 at TSC1, rs249942 at PALB2, and rs9827843 at ROBO2) did not achieve significance in a stage 2meta-analysis performed in 56,246 additional independent individuals, indicating that these common SNPs are not associated with estimated GFR. The effect of less common or rare variants in these genes on kidney function in the general population and disease-specific cohorts requires further research. Copyright Â© 2013 by the American Society of Nephrology.
|2013||Kottgen 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]|
|2013||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]|
|2013||Magee CA, Holliday EG, Attia JR, Kritharides L, Banks E, 'Investigation of the relationship between sleep duration, all-cause mortality, and preexisting disease', Sleep Medicine, 14 591-596 (2013) [C1]|
|2013||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]|
|2013||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]|
|2013||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]|
|2013||Holliday EG, Magee CA, Kritharides L, Banks E, Attia J, 'Short Sleep Duration Is Associated with Risk of Future Diabetes but Not Cardiovascular Disease: a Prospective Study and Meta-Analysis', PLOS ONE, 8 (2013) [C1]|
|2013||Sun C, Young TL, Mackey DA, Van Zuydam NR, Doney ASF, Palmer CNA, et al., 'Genetic loci for retinal arteriolar microcirculation', PLoS One, 8 e65804 (2013) [C1]|
|2013||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 e54232 (2013) [C1]|
|2013||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 e53830 (2013) [C1]|
|2013||Holliday EG, 'Hints of unique genetic effects for type 2 diabetes in India', Diabetes, 62 1369-1370 (2013) [C1]|
|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]|
|2012||Bellenguez C, Bevan S, Gschwendtner A, Spencer CCA, Burgess AI, Pirinen M, et al., 'Genome-wide association study identifies a variant in HDAC9 associated with large vessel ischemic stroke', Nature Genetics, 44 328-333 (2012) [C1]|
|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]|
|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]|
|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]|
|2012||Chasman DI, Fuchsberger C, Pattaro C, Teumer A, Boger CA, Endlich K, et al., 'Integration of genome-wide association studies with biological knowledge identifies six novel genes related to kidney function', Human Molecular Genetics, 21 5329-5343 (2012) [C1]|
|2012||Traylor M, Farrall M, Holliday EG, Sudlow C, Hopewell JC, Cheng Y-C, et al., 'Genetic risk factors for ischaemic stroke and its subtypes (the METASTROKE Collaboration): A meta-analysis of genome-wide association studies', The Lancet Neurology, 11 951-962 (2012) [C1]|
|2012||Pattaro C, Kottgen A, Teumer A, Garnaas M, Boger CA, Fuchsberger C, et al., 'Genome-wide association and functional follow-up reveals new loci for kidney function', PLOS Genetics, 8 1-15 (2012) [C1]|
|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]|| |
|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]|| |
|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]|| |
|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]|
|2009||Thara R, Tirupati S, John S, Nancarrow D, Chant D, Holliday E, Mowry B, 'Design and clinical characteristics of a homogeneous schizophrenia pedigree sample from Tamil Nadu, India', Australian and New Zealand Journal of Psychiatry, 43 561-570 (2009) [C1]|| |