2024 |
Quinn TP, Hess JL, Marshe VS, Barnett MM, Hauschild A-C, Maciukiewicz M, et al., 'A primer on the use of machine learning to distil knowledge from data in biological psychiatry', Molecular Psychiatry, [C1]
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2024 |
Jameei H, Rakesh D, Zalesky A, Cairns MJ, Reay WR, Wray NR, Di Biase MA, 'Linking Polygenic Risk of Schizophrenia to Variation in Magnetic Resonance Imaging Brain Measures: A Comprehensive Systematic Review.', Schizophr Bull, 50 32-46 (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 |
Duchatel RJ, Jackson ER, Parackal SG, Kiltschewskij D, Findlay IJ, Mannan A, et al., 'PI3K/mTOR is a therapeutically targetable genetic dependency in diffuse intrinsic pontine glioma.', J Clin Invest, (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 |
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 |
Reay WR, Kiltschewskij DJ, Di Biase MA, Gerring ZF, Kundu K, Surendran P, et al., 'Genetic influences on circulating retinol and its relationship to human health', Nature Communications, 15
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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 |
Adams DM, Reay WR, Cairns MJ, 'Multiomic prioritisation of risk genes for anorexia nervosa', Psychological Medicine, 53 6754-6762 (2023) [C1]
Background Anorexia nervosa (AN) is a psychiatric disorder associated with marked morbidity. Whilst AN genetic studies could identify novel treatment targets, integration of funct... [more]
Background Anorexia nervosa (AN) is a psychiatric disorder associated with marked morbidity. Whilst AN genetic studies could identify novel treatment targets, integration of functional genomics data, including transcriptomics and proteomics, would assist to disentangle correlated signals and reveal causally associated genes. Methods We used models of genetically imputed expression and splicing from 14 tissues, leveraging mRNA, protein, and mRNA alternative splicing weights to identify genes, proteins, and transcripts, respectively, associated with AN risk. This was accomplished through transcriptome, proteome, and spliceosome-wide association studies, followed by conditional analysis and finemapping to prioritise candidate causal genes. Results We uncovered 134 genes for which genetically predicted mRNA expression was associated with AN after multiple-testing correction, as well as four proteins and 16 alternatively spliced transcripts. Conditional analysis of these significantly associated genes on other proximal association signals resulted in 97 genes independently associated with AN. Moreover, probabilistic finemapping further refined these associations and prioritised putative causal genes. The gene WDR6, for which increased genetically predicted mRNA expression was correlated with AN, was strongly supported by both conditional analyses and finemapping. Pathway analysis of genes revealed by finemapping identified the pathway regulation of immune system process (overlapping genes = MST1, TREX1, PRKAR2A, PROS1) as statistically overrepresented. Conclusions We leveraged multiomic datasets to genetically prioritise novel risk genes for AN. Multiple-lines of evidence support that WDR6 is associated with AN, whilst other prioritised genes were enriched within immune related pathways, further supporting the role of the immune system in AN.
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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 |
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, (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 |
Barnett MM, Reay WR, Geaghan MP, Kiltschewskij DJ, Green MJ, Weidenhofer J, et al., 'miRNA cargo in circulating vesicles from neurons is altered in individuals with schizophrenia and associated with severe disease.', Sci Adv, 9 eadi4386 (2023) [C1]
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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 |
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, S0006-3223(23)01433-6 (2023) [C1]
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2023 |
Mahmoudi E, Cairns MJ, 'CircRNA and Ageing 249-270 (2023) [C1]
Circular RNAs (circRNAs) are closed-loop RNA transcripts formed by a noncanonical back splicing mechanism. circRNAs are expressed in various tissues and cell types in a temporospa... [more]
Circular RNAs (circRNAs) are closed-loop RNA transcripts formed by a noncanonical back splicing mechanism. circRNAs are expressed in various tissues and cell types in a temporospatially regulated manner and have diverse molecular functions including their ability to act as miRNA sponges, transcriptional and splicing regulators, protein traps, and even templates for polypeptide synthesis. Emerging evidence suggests that circRNAs are themselves dynamically regulated throughout development in various organisms, with a substantial accumulation during ageing. Their regulatory roles in cellular pathways associated with ageing and senescence, as well as their implications in ageing-related diseases, such as neurological disease, cancer, and cardiovascular disease, suggest that circRNAs are key molecular determinants of the ageing process. Their unique structure, expression specificity, and biological functions highlight a potential capacity for use as novel biomarkers for diagnosis, prognosis, and treatment outcomes in a variety of conditions including pathological ageing. CircRNA may also have potential as target for interventions that manipulate ageing and longevity. In this chapter, we discuss the most recent advances in circRNA changes in ageing and ageing-associated disease.
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2023 |
Ballinger ML, Pattnaik S, Mundra PA, Zaheed M, Rath E, Priestley P, et al., 'Heritable defects in telomere and mitotic function selectively predispose to sarcomas.', Science, 379 253-260 (2023) [C1]
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2023 |
Greco L, 'Exploring opportunities for drug repurposing and precision medicine in cannabis use disorder using genetics', Addiction Biology, (2023) [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 |
Kiltschewskij DJ, Harrison PF, Fitzsimmons C, Beilharz TH, Cairns MJ, 'Extension of mRNA poly(A) tails and 3'UTRs during neuronal differentiation exhibits variable association with post-transcriptional dynamics.', Nucleic Acids Res, 51 8181-8198 (2023) [C1]
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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 |
Su M, Pan T, Chen QZ, Zhou WW, Gong Y, Xu G, et al., 'Data analysis guidelines for single-cell RNA-seq in biomedical studies and clinical applications', Military Medical Research, 9 (2022) [C1]
The application of single-cell RNA sequencing (scRNA-seq) in biomedical research has advanced our understanding of the pathogenesis of disease and provided valuable insights into ... [more]
The application of single-cell RNA sequencing (scRNA-seq) in biomedical research has advanced our understanding of the pathogenesis of disease and provided valuable insights into new diagnostic and therapeutic strategies. With the expansion of capacity for high-throughput scRNA-seq, including clinical samples, the analysis of these huge volumes of data has become a daunting prospect for researchers entering this field. Here, we review the workflow for typical scRNA-seq data analysis, covering raw data processing and quality control, basic data analysis applicable for almost all scRNA-seq data sets, and advanced data analysis that should be tailored to specific scientific questions. While summarizing the current methods for each analysis step, we also provide an online repository of software and wrapped-up scripts to support the implementation. Recommendations and caveats are pointed out for some specific analysis tasks and approaches. We hope this resource will be helpful to researchers engaging with scRNA-seq, in particular for emerging clinical applications.
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2022 |
Marin FR, Dávalos A, Kiltschewskij D, Crespo MC, Cairns M, Andrés-León E, Soler-Rivas C, 'RNA-Seq, Bioinformatic Identification of Potential MicroRNA-Like Small RNAs in the Edible Mushroom Agaricus bisporus and Experimental Approach for Their Validation', International Journal of Molecular Sciences, 23 (2022) [C1]
Although genomes from many edible mushrooms are sequenced, studies on fungal micro RNAs (miRNAs) are scarce. Most of the bioinformatic tools are designed for plants or animals, bu... [more]
Although genomes from many edible mushrooms are sequenced, studies on fungal micro RNAs (miRNAs) are scarce. Most of the bioinformatic tools are designed for plants or animals, but the processing and expression of fungal miRNAs share similarities and differences with both kingdoms. Moreover, since mushroom species such as Agaricus bisporus (A. bisporus, white button mushroom) are frequently consumed as food, controversial discussions are still evaluating whether their miRNAs might or might not be assimilated, perhaps within extracellular vesicles (i.e., exosomes). Therefore, the A. bisporus RNA-seq was studied in order to identify potential de novo miRNA-like small RNAs (milRNAs) that might allow their later detection in diet. Results pointed to 1 already known and 37 de novo milRNAs. Three milRNAs were selected for RT-qPCR experiments. Precursors and mature milRNAs were found in the edible parts (caps and stipes), validating the predictions carried out in silico. When their potential gene targets were investigated, results pointed that most were involved in primary and secondary metabolic regulation. However, when the human transcriptome is used as the target, the results suggest that they might interfere with important biological processes related with cancer, infection and neurodegenerative diseases.
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2022 |
Reay WR, Geaghan MP, Atkins JR, Carr VJ, Green MJ, Cairns MJ, 'Genetics-informed precision treatment formulation in schizophrenia and bipolar disorder', AMERICAN JOURNAL OF HUMAN GENETICS, 109 1620-1637 (2022) [C1]
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2022 |
Tonini E, Watkeys O, Quide Y, Whitford TJ, Cairns MJ, Green MJ, 'Polygenic risk for schizophrenia as a moderator of associations between childhood trauma and schizotypy', PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY, 119 (2022) [C1]
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Nova |
2022 |
Reay WR, Haslam R, Cairns MJ, Moschonis G, Clarke E, Attia J, Collins CE, 'Variation in cardiovascular disease risk factors among older adults in the Hunter Community Study cohort: A comparison of diet quality versus polygenic risk score', JOURNAL OF HUMAN NUTRITION AND DIETETICS, 35 675-688 (2022) [C1]
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Nova |
2022 |
Cullen MBR, Meiser B, Barlow-Stewart K, Green M, Appelbaum PS, Carr VJ, et al., 'Perceptions of causal attribution and attitudes to genetic testing among people with schizophrenia and their first-degree relatives', EUROPEAN JOURNAL OF HUMAN GENETICS, 30 1147-1154 (2022) [C1]
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2022 |
Geaghan MP, Reay WR, Cairns MJ, 'MicroRNA binding site variation is enriched in psychiatric disorders', HUMAN MUTATION, 43 2153-2169 (2022) [C1]
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Nova |
2022 |
Reay WR, Kiltschewskij DJ, Geaghan MP, Atkins JR, Carr VJ, Green MJ, Cairns MJ, 'Genetic estimates of correlation and causality between blood-based biomarkers and psychiatric disorders', SCIENCE ADVANCES, 8 (2022) [C1]
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2022 |
Reay WR, Geaghan MP, Cairns MJ, 'The genetic architecture of pneumonia susceptibility implicates mucin biology and a relationship with psychiatric illness', NATURE COMMUNICATIONS, 13 (2022) [C1]
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2022 |
Quide Y, Watkeys OJ, Girshkin L, Kaur M, Carr VJ, Cairns MJ, Green MJ, 'Interactive effects of polygenic risk and cognitive subtype on brain morphology in schizophrenia spectrum and bipolar disorders', EUROPEAN ARCHIVES OF PSYCHIATRY AND CLINICAL NEUROSCIENCE, 272 1205-1218 (2022) [C1]
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2022 |
Kiltschewskij DJ, Reay WR, Cairns MJ, 'Evidence of genetic overlap and causal relationships between blood-based biochemical traits and human cortical anatomy', TRANSLATIONAL PSYCHIATRY, 12 (2022) [C1]
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Nova |
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 |
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 |
Aparecida Nedel Pertile R, Kiltschewskij D, Geaghan M, Barnett M, Cui X, Cairns MJ, Eyles D, 'Developmental vitamin D-deficiency increases the expression of microRNAs involved in dopamine neuron development', Brain Research, 1789 (2022) [C1]
Schizophrenia is a neurodevelopmental disorder associated with abnormal dopamine (DA) signalling and disruptions in early brain development. We have shown that developmental vitam... [more]
Schizophrenia is a neurodevelopmental disorder associated with abnormal dopamine (DA) signalling and disruptions in early brain development. We have shown that developmental vitamin D-deficiency (DVD-deficiency) increases the risk of schizophrenia in offspring and impairs various aspects of brain development in rodents, particularly that of DA neurons, however the molecular basis of these impairments remains unclear. Here, we explore whether small non-coding microRNAs (miRNAs) are involved. miRNAs regulate gene expression post-transcriptionally via translational repression and destabilisation of mRNA. While dysregulation of multiple miRNAs has been reported in post-mortem brain of patients with schizophrenia, the biological pathways affected by these small RNAs are not clear. Here we identified differential expression of 18 miRNAs in DA neurons isolated from DVD-deficient embryos. Three miRNAs were selected for further functional studies of dopaminergic neuron differentiation based on their interactions with transcripts involved in neuronal maturation. In particular, we show upregulation of miR-181c-5p suppresses neurite outgrowth of dopaminergic neurons. These findings provide further evidence that an environmental risk factor for schizophrenia ¿ DVD-deficiency ¿ disrupts the development of DA neurons and suggests increased miRNA expression may be one possible mechanism. This disruption potentially underlies the long-term alterations in DA mediated brain function in DVD-deficient offspring, and by inference in schizophrenia.
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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 |
Di Biase MA, Geaghan MP, Reay WR, Seidlitz J, Weickert CS, Pébay A, et al., 'Cell type-specific manifestations of cortical thickness heterogeneity in schizophrenia', Molecular Psychiatry, 27 2052-2060 (2022) [C1]
Brain morphology differs markedly between individuals with schizophrenia, but the cellular and genetic basis of this heterogeneity is poorly understood. Here, we sought to determi... [more]
Brain morphology differs markedly between individuals with schizophrenia, but the cellular and genetic basis of this heterogeneity is poorly understood. Here, we sought to determine whether cortical thickness (CTh) heterogeneity in schizophrenia relates to interregional variation in distinct neural cell types, as inferred from established gene expression data and person-specific genomic variation. This study comprised 1849 participants in total, including a discovery (140 cases and 1267 controls) and a validation cohort (335 cases and 185 controls). To characterize CTh heterogeneity, normative ranges were established for 34 cortical regions and the extent of deviation from these ranges was measured for each individual with schizophrenia. CTh deviations were explained by interregional gene expression levels of five out of seven neural cell types examined: (1) astrocytes; (2) endothelial cells; (3) oligodendrocyte progenitor¿cells (OPCs); (4) excitatory¿neurons; and (5) inhibitory neurons. Regional alignment between CTh alterations with cell type transcriptional maps distinguished broad patient subtypes, which were validated against genomic data drawn from the same individuals. In a predominantly neuronal/endothelial subtype (22% of patients), CTh deviations covaried with polygenic risk for schizophrenia (sczPRS) calculated specifically from genes marking neuronal and endothelial cells (r = -0.40, p = 0.010). Whereas, in a predominantly glia/OPC subtype (43% of patients), CTh deviations covaried with sczPRS calculated from glia and OPC-linked genes (r = -0.30, p = 0.028). This multi-scale analysis of genomic, transcriptomic, and brain phenotypic data may indicate that CTh heterogeneity in schizophrenia relates to inter-individual variation in cell-type specific functions. Decomposing heterogeneity in relation to cortical cell types enables prioritization of schizophrenia subsets for future disease modeling efforts.
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2022 |
Greco LA, Reay WR, Dayas C, Cairns MJ, 'Pairwise genetic meta-analyses between schizophrenia and substance dependence phenotypes reveals novel association signals with pharmacological significance', TRANSLATIONAL PSYCHIATRY, 12 (2022) [C1]
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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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Nova |
2021 |
Adams DM, Reay WR, Geaghan MP, Cairns MJ, 'Investigation of glycaemic traits in psychiatric disorders using Mendelian randomisation revealed a causal relationship with anorexia nervosa', NEUROPSYCHOPHARMACOLOGY, 46 1093-1102 (2021) [C1]
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Nova |
2021 |
Mahmoudi E, Atkins JR, Quide Y, Reay WR, Cairns HM, Fitzsimmons C, et al., 'The
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Nova |
2021 |
Mahmoudi E, Green MJ, Cairns MJ, 'Dysregulation of circRNA expression in the peripheral blood of individuals with schizophrenia and bipolar disorder', Journal of Molecular Medicine, 99 981-991 (2021) [C1]
Abstract: Circular RNAs (circRNAs) are head-to-tail back-spliced RNA transcripts that have been linked to several biological processes and their perturbation is evident in human d... [more]
Abstract: Circular RNAs (circRNAs) are head-to-tail back-spliced RNA transcripts that have been linked to several biological processes and their perturbation is evident in human disease, including neurological disorders. There is also emerging research suggesting circRNA expression may also be altered in psychiatric and behavioural syndromes. Here, we provide a comprehensive analysis of circRNA expression in peripheral blood mononuclear cells (PBMCs) from 39 patients with schizophrenia and bipolar disorder as well as 20 healthy individuals using deep RNA-seq. We observed systematic alternative splicing leading to a complex and diverse profile of RNA transcripts including 8762 high confidence circRNAs. More specific scrutiny of the circular transcriptome in schizophrenia and bipolar disorder, compared to a non-psychiatric control group, revealed significant dysregulation of 55 circRNAs with a bias towards downregulation. These molecules were predicted to interact with a large number of miRNAs that target genes enriched in psychiatric disorders. Further replication and cross-validation to determine the specificity of these circRNAs across broader diagnostic groups and subgroups in psychiatry will enable their potential utility as biomarkers to be established. Key messages: ¿ We identified 8762 high confidence circRNAs with systematic alternative splicing in human PBMCs. ¿ CircRNAs were dysregulated in schizophrenia and bipolar disorder, compared to a non-psychiatric control group. ¿ The DE circRNAs were predicted to interact with miRNAs with target genes enriched in psychiatric disorders. ¿ Some circRNAs have the potential to serve as biomarkers in psychiatry.
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2021 |
Reay WR, Cairns MJ, 'Advancing the use of genome-wide association studies for drug repurposing', NATURE REVIEWS GENETICS, 22 658-671 (2021) [C1]
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Nova |
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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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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2020 |
Reay WR, Atkins JR, Carr VJ, Green MJ, Cairns MJ, 'Pharmacological enrichment of polygenic risk for precision medicine in complex disorders', SCIENTIFIC REPORTS, 10 (2020) [C1]
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Nova |
2020 |
Kiltschewskij DJ, Geaghan MP, Cairns MJ, 'Characterising the Transcriptional and Translational Impact of the Schizophrenia-Associated miR-1271-5p in Neuronal Cells', CELLS, 9 (2020) [C1]
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Nova |
2020 |
Kiltschewskij DJ, Cairns MJ, 'Transcriptome-wide analysis of interplay between mrna stability, translation and small RNAs in response to neuronal membrane depolarization', International Journal of Molecular Sciences, 21 1-23 (2020) [C1]
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Nova |
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 |
Reay WR, Cairns MJ, 'The role of the retinoids in schizophrenia: genomic and clinical perspectives', Molecular Psychiatry, 25 706-718 (2020) [C1]
Signalling by retinoid compounds is vital for embryonic development, with particular importance for neurogenesis in the human brain. Retinoids, metabolites of vitamin A, exert inf... [more]
Signalling by retinoid compounds is vital for embryonic development, with particular importance for neurogenesis in the human brain. Retinoids, metabolites of vitamin A, exert influence over the expression of thousands of transcripts genome wide, and thus, act as master regulators of many important biological processes. A significant body of evidence in the literature now supports dysregulation of the retinoid system as being involved in the aetiology of schizophrenia. This includes mechanistic insights from large-scale genomic, transcriptomic and, proteomic studies, which implicate disruption of disparate aspects of retinoid biology such as transport, metabolism, and signalling. As a result, retinoids may present a valuable clinical opportunity in schizophrenia via novel pharmacotherapies and dietary intervention. Further work, however, is required to expand on the largely observational data collected thus far and confirm causality. This review will highlight the fundamentals of retinoid biology and examine the evidence for retinoid dysregulation in schizophrenia.
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Nova |
2020 |
Mahmoudi E, Kiltschewskij D, Fitzsimmons C, Cairns MJ, 'Depolarization-Associated CircRNA Regulate Neural Gene Expression and in Some Cases May Function as Templates for Translation', CELLS, 9 (2020) [C1]
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Nova |
2020 |
Pinese M, Lacaze P, Rath EM, Stone A, Brion MJ, Ameur A, et al., 'The Medical Genome Reference Bank contains whole genome and phenotype data of 2570 healthy elderly', Nature Communications, 11 1-14 (2020) [C1]
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Nova |
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 |
Reay WR, Cairns MJ, 'Pairwise common variant meta-analyses of schizophrenia with other psychiatric disorders reveals shared and distinct gene and gene-set associations', TRANSLATIONAL PSYCHIATRY, 10 (2020) [C1]
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Nova |
2020 |
Khavari B, Cairns MJ, 'Epigenomic Dysregulation in Schizophrenia: In Search of Disease Etiology and Biomarkers.', Cells, 9 (2020) [C1]
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Nova |
2020 |
Khavari B, Mahmoudi E, Geaghan MP, Cairns MJ, 'Oxidative Stress Impact on the Transcriptome of Differentiating Neuroblastoma Cells: Implication for Psychiatric Disorders.', International Journal of Molecular Sciences, 21 1-17 (2020) [C1]
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Nova |
2020 |
Bond DR, Kahl R, Brzozowski JS, Jankowski H, Naudin C, Pariyar M, et al., 'Tetraspanin CD9 is regulated by MiR-518f-5p and functions in breast cell migration and in vivo tumor growth', Cancers, 12 (2020) [C1]
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Nova |
2020 |
Adams D, Reay W, Geaghan M, Cairns M, 'Investigating the effect of glycaemic traits on the risk of psychiatric illness using Mendelian randomisation (2020)
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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 |
Reay WR, Atkins JR, Quidé Y, Carr VJ, Green MJ, Cairns MJ, 'Polygenic disruption of retinoid signalling in schizophrenia and a severe cognitive deficit subtype', Molecular Psychiatry, 25 719-731 (2020) [C1]
Retinoid metabolites of vitamin A are intrinsically linked to neural development, connectivity and plasticity, and have been implicated in the pathophysiology of schizophrenia. We... [more]
Retinoid metabolites of vitamin A are intrinsically linked to neural development, connectivity and plasticity, and have been implicated in the pathophysiology of schizophrenia. We hypothesised that a greater burden of common and rare genomic variation in genes involved with retinoid biogenesis and signalling could be associated with schizophrenia and its cognitive symptoms. Common variants associated with schizophrenia in the largest genome-wide association study were aggregated in retinoid genes and used to formulate a polygenic risk score (PRSRet) for each participant in the Australian Schizophrenia Research Bank. In support of our hypothesis, we found PRSRet to be significantly associated with the disorder. Cases with severe cognitive deficits, while not further differentiated by PRSRet, were enriched with rare variation in the retinoic acid receptor beta gene RARB, detected through whole-genome sequencing. RARB rare variant burden was also associated with reduced cerebellar volume in the cases with marked cognitive deficit, and with covariation in grey matter throughout the brain. An excess of rare variation was further observed in schizophrenia in retinoic acid response elements proximal to target genes, which we show are differentially expressed in the disorder in two RNA sequencing datasets. Our results suggest that genomic variation may disrupt retinoid signalling in schizophrenia, with particular significance for cases with severe cognitive impairment.
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Nova |
2020 |
Watkeys OJ, Cohen-Woods S, Quide Y, Cairns MJ, Overs B, Fullerton JM, Green MJ, 'Derivation of poly-methylomic pro fi le scores for schizophrenia', PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY, 101 (2020) [C1]
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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 |
2019 |
Kiltschewskij D, Cairns MJ, 'Temporospatial guidance of activity-dependent gene expression by microRNA: mechanisms and functional implications for neural plasticity.', Nucleic acids research, 47 533-545 (2019) [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 |
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 |
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 |
Reay W, Atkins J, Carr V, Green M, Cairns M, 'Pharmacological enrichment of polygenic risk for precision medicine in complex disorders (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 |
Wang X, Cairns MJ, Yan J, 'Super-enhancers in transcriptional regulation and genome organization', Nucleic Acids Research, 47 11481-11496 (2019) [C1]
Gene expression is precisely controlled in a stage and cell-type-specific manner, largely through the interaction between cis-regulatory elements and their associated trans-acting... [more]
Gene expression is precisely controlled in a stage and cell-type-specific manner, largely through the interaction between cis-regulatory elements and their associated trans-acting factors. Where these components aggregate in promoters and enhancers, they are able to cooperate to modulate chromatin structure and support the engagement in long-range 3D superstructures that shape the dynamics of a cell's genomic architecture. Recently, the term 'super-enhancer' has been introduced to describe a hyper-active regulatory domain comprising a complex array of sequence elements that work together to control the key gene networks involved in cell identity. Here, we survey the unique characteristics of super-enhancers compared to other enhancer types and summarize the recent advances in our understanding of their biological role in gene regulation. In particular, we discuss their capacity to attract the formation of phase-separated condensates, and capacity to generate three-dimensional genome structures that precisely activate their target genes. We also propose a multi-stage transition model to explain the evolutionary pressure driving the development of super-enhancers in complex organisms, and highlight the potential for involvement in tumorigenesis. Finally, we discuss more broadly the role of super-enhancers in human health disorders and related potential in therapeutic interventions.
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Nova |
2019 |
Santarelli DM, Carroll AP, Cairns HM, Tooney PA, Cairns MJ, 'Schizophrenia -associated MicroRNA?Gene Interactions in the Dorsolateral Prefrontal Cortex', GENOMICS PROTEOMICS & BIOINFORMATICS, 17 623-634 (2019) [C1]
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Nova |
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 |
Cairns MJ, 'Small RNA regulators of social behaviour in eutherian mammals', EMBO Reports, 20 1-3 (2019)
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Nova |
2019 |
Mahmoudi E, Cairns MJ, 'Circular RNAs are temporospatially regulated throughout development and ageing in the rat', SCIENTIFIC REPORTS, 9 (2019) [C1]
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Nova |
2019 |
Nakamura JP, Schroeder A, Hudson M, Jones N, Gillespie B, Du X, et al., 'The maternal immune activation model uncovers a role for the Arx gene in GABAergic dysfunction in schizophrenia', Brain, Behavior, and Immunity, 81 161-171 (2019) [C1]
A hallmark feature of schizophrenia is altered high frequency neural oscillations, including reduced auditory-evoked gamma oscillatory power, which is underpinned by parvalbumin (... [more]
A hallmark feature of schizophrenia is altered high frequency neural oscillations, including reduced auditory-evoked gamma oscillatory power, which is underpinned by parvalbumin (PV) interneuron dysfunction. Maternal immune activation (MIA) in rodents models an environmental risk factor for schizophrenia and recapitulates these PV interneuron changes. This study sought to link reduced PV expression in the MIA model with alterations to auditory-evoked gamma oscillations and transcript expression. We further aligned transcriptional findings from the animal model with human genome sequencing data. We show that MIA, induced by the viral mimetic, poly-I:C in C57Bl/6 mice, caused in adult offspring reduced auditory-evoked gamma and theta oscillatory power paralleled by reduced PV protein levels. We then showed the Arx gene, critical to healthy neurodevelopment of PV interneurons, is reduced in the forebrain of MIA exposed mice. Finally, in a whole-genome sequenced patient cohort, we identified a novel missense mutation of ARX in a patient with schizophrenia and in the Psychiatric Genomics Consortium 2 cohort, a nominal association of proximal ARX SNPs with the disorder. This suggests MIA, as a risk factor for schizophrenia, may be influencing Arx expression to induce the GABAergic dysfunction seen in schizophrenia and that the ARX gene may play a role in the prenatal origins of schizophrenia pathophysiology.
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Nova |
2019 |
Mahmoudi E, Fitzsimmons C, Geaghan MP, Shannon Weickert C, Atkins JR, Wang X, Cairns MJ, 'Circular RNA biogenesis is decreased in postmortem cortical gray matter in schizophrenia and may alter the bioavailability of associated miRNA', Neuropsychopharmacology, 44 1043-1054 (2019) [C1]
Circular RNAs (circRNAs) are a covalently closed subclass of non-coding RNA molecules formed by back splicing of linear precursor RNA. These molecules are relatively stable and pa... [more]
Circular RNAs (circRNAs) are a covalently closed subclass of non-coding RNA molecules formed by back splicing of linear precursor RNA. These molecules are relatively stable and particularly abundant in the mammalian brain and therefore may participate in neural development and function. With the emergence of circRNAs activity in gene regulation, these molecules have been implicated in several biological processes, including synaptic plasticity, and we therefore suspect they may have a role in neurobehavioral disorders. Here, we profile cortical circRNAs expression in 35 postmortem cortical gray matter (BA46) schizophrenia and a non-psychiatric comparison group, using circRNA enrichment sequencing. While more than 90,000 circRNAs species were identified in the dorsolateral prefrontal cortex (DLPFC), we observed lower complexity and substantial depletion in subjects with the disorder. Although circRNAs expression was independent of their host gene transcription, alternative splicing rates were lower in samples from cases compared to controls. Gene set analysis of differentially expressed circRNAs host genes revealed significant enrichment of neural functions and neurological disorders. Many of these depleted circRNAs are also predicted to sequester miRNAs that were shown previously to be increased in the disorder, potentially exacerbating the functional impact of their dysregulation through posttranscriptional gene silencing. While this is the first reported exploration of circRNAs in schizophrenia, there is significant potential for dysregulation more broadly in other major mental illnesses and behavioral disorders. Given their capacity for modulating miRNA function, circRNA may play a significant role in the pathophysiology of disease and even be targeted for therapeutic manipulation.
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Nova |
2018 |
Gusev A, Mancuso N, Won H, Kousi M, Finucane HK, Reshef Y, et al., 'Transcriptome-wide association study of schizophrenia and chromatin activity yields mechanistic disease insights', NATURE GENETICS, 50 538-+ (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 |
Quidé Y, Matosin N, Atkins JR, Fitzsimmons C, Cairns MJ, Carr VJ, Green MJ, 'Common variation in ZNF804A (rs1344706) is not associated with brain morphometry in schizophrenia or healthy participants', Progress in Neuro-Psychopharmacology and Biological Psychiatry, 82 12-20 (2018) [C1]
Background The single nucleotide polymorphism (SNP) rs1344706 [A > C] within intron 2 of the zinc finger protein 804A gene (ZNF804A) is associated with schizophrenia at the gen... [more]
Background The single nucleotide polymorphism (SNP) rs1344706 [A > C] within intron 2 of the zinc finger protein 804A gene (ZNF804A) is associated with schizophrenia at the genome-wide level, but its function in relation to the development of psychotic disorders, including its influence on brain morphology remains unclear. Methods Using both univariate (voxel-based morphometry, VBM; cortical thickness) and multivariate (source-based morphometry, SBM) approaches, we examined the effects of variation of the rs1344706 polymorphism on grey matter integrity in 214 Caucasian schizophrenia cases and 94 Caucasian healthy individuals selected from the Australian Schizophrenia Research Bank. Results Neither univariate nor multivariate analyses showed any associations between indices of grey matter and rs1344706 variation in schizophrenia or healthy participants. This was revealed in the context of the typical pattern of decreased grey matter integrity in schizophrenia compared to healthy individuals, including: (1) large grey matter volume reductions in the orbitofrontal and anterior cingulate cortices and the left fusiform/inferior temporal gyri; (2) decreased cortical thickness in the left inferior temporal and fusiform gyri, the left orbitofrontal gyrus, as well as in the right pars opercularis/precentral gyrus; and (3) decreased covariation of grey matter concentration in frontal and limbic brain regions emerging from the SBM analyses. Conclusions Contrary to some ¿ but not all ¿ previous findings, this study of a large sample of schizophrenia cases and healthy controls reveals no evidence for association between grey matter alterations and variation in rs1344706 (ZNF804A). Differences in sample sizes and ethnicities may account for discrepant findings between the present and previous studies.
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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 ST8S/A2 haplotype on cerebral white matter diffusion properties in schizophrenia and healthy controls', TRANSLATIONAL PSYCHIATRY, 8 (2018) [C1]
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Nova |
2018 |
Quinn RK, James MH, Hawkins GE, Brown AL, Heathcote A, Smith DW, et al., 'Temporally specific miRNA expression patterns in the dorsal and ventral striatum of addiction-prone rats', Addiction Biology, 23 631-642 (2018) [C1]
MicroRNAs (miRNAs) within the ventral and dorsal striatum have been shown to regulate addiction-relevant behaviours. However, it is unclear how cocaine experience alone can alter ... [more]
MicroRNAs (miRNAs) within the ventral and dorsal striatum have been shown to regulate addiction-relevant behaviours. However, it is unclear how cocaine experience alone can alter the expression of addiction-relevant miRNAs within striatal subregions. Further, it is not known whether differential expression of miRNAs in the striatum contributes to individual differences in addiction vulnerability. We first examined the effect of cocaine self-administration on the expression of miR-101b, miR-137, miR-212 and miR-132 in nucleus accumbens core and nucleus accumbens shell (NAcSh), as well as dorsomedial striatum and dorsolateral striatum (DLS). We then examined the expression of these same miRNAs in striatal subregions of animals identified as being ¿addiction-prone¿, either immediately following self-administration training or following extinction and relapse testing. Cocaine self-administration was associated with changes in miRNA expression in a regionally discrete manner within the striatum, with the most marked changes occurring in the nucleus accumbens core. When we examined the miRNA profile of addiction-prone rats following self-administration, we observed increased levels of miR-212 in the dorsomedial striatum. After extinction and relapse testing, addiction-prone rats showed significant increases in the expression of miR-101b, miR-137, miR-212 and miR-132 in NAcSh, and miR-137 in the DLS. This study identifies temporally specific changes in miRNA expression consistent with the engagement of distinct striatal subregions across the course of the addiction cycle. Increased dysregulation of miRNA expression in NAcSh and DLS at late stages of the addiction cycle may underlie habitual drug seeking, and may therefore aid in the identification of targets designed to treat addiction.
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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 |
Bond DR, Naudin C, Carroll AP, Goldie BJ, Brzozowski JS, Jankowski HM, et al., 'miR-518f-5p decreases tetraspanin CD9 protein levels and differentially affects non-tumourigenic prostate and prostate cancer cell migration and adhesion', ONCOTARGET, 9 1980-1991 (2018) [C1]
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Nova |
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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Nova |
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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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 |
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 |
Sahoo SS, Quah MY, Nielsen S, Atkins J, Au GG, Cairns MJ, et al., 'Inhibition of extracellular matrix mediated TGF-ß signalling suppresses endometrial cancer metastasis.', Oncotarget, 8 (2017) [C1]
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Nova |
2017 |
Mahmoudi E, Cairns MJ, 'MiR-137: An important player in neural development and neoplastic transformation', Molecular Psychiatry, 22 44-55 (2017) [C1]
MicroRNAs (miRNAs) represent an important class of small regulatory RNAs that control gene expression posttranscriptionally by targeting mRNAs for degradation or translation inhib... [more]
MicroRNAs (miRNAs) represent an important class of small regulatory RNAs that control gene expression posttranscriptionally by targeting mRNAs for degradation or translation inhibition. Early studies have revealed a complex role for miRNAs in major biological processes such as development, differentiation, growth and metabolism. MiR-137 in particular, has been of great interest due to its critical role in brain function and putative involvement in the etiology of both neuropsychiatric disorders and cancer. Several lines of evidence suggest that development, differentiation and maturation of the nervous system is strongly linked to the expression of miR-137 and its regulation of a large number of downstream target genes in various pathways. Dysregulation of this molecule has also been implicated in major mental illnesses through its position in a variant allele highly associated with schizophrenia in the largest mega genome-wide association studies. Interestingly, miR-137 has also been shown to act as a tumor suppressor, with numerous studies finding reduced expression in neoplasia including brain tumor. Restoration of miR-137 expression has also been shown to inhibit cell proliferation, migration and metastasis, and induce cell cycle arrest, differentiation and apoptosis. These properties of miR-137 propose its potential for prognosis, diagnosis and as a therapeutic target for treatment of several human neurological and neoplastic disorders. In this review, we provide details on the discovery, targets, function, regulation and disease involvement of miR-137 with a broad look at recent discovery in this area.
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Nova |
2017 |
Goldie BJ, Fitzsimmons C, Weidenhofer J, Atkins JR, Wang DO, Cairns MJ, 'miRNA Enriched in Human Neuroblast Nuclei Bind the MAZ Transcription Factor and Their Precursors Contain the MAZ Consensus Motif', FRONTIERS IN MOLECULAR NEUROSCIENCE, 10 (2017) [C1]
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Nova |
2016 |
Hollins S, Walker F, cairns M, 'Small RNA regulation of neural gene expression in response to environmental exposure associated with neuropsychiatric syndromes', RNA & DISEASE, 3 (2016) [C1]
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Nova |
2016 |
Kumar M, Atkins J, Cairns M, Ali A, Tanwar PS, 'Germ cell-specific sustained activation of Wnt signalling perturbs spermatogenesis in aged mice, Possibly through non-coding RNAs', Oncotarget, 7 85709-85727 (2016) [C1]
Dysregulated Wnt signalling is associated with human infertility and testicular cancer. However, the role of Wnt signalling in male germ cells remains poorly understood. In this s... [more]
Dysregulated Wnt signalling is associated with human infertility and testicular cancer. However, the role of Wnt signalling in male germ cells remains poorly understood. In this study, we first confirmed the activity of Wnt signalling in mouse, dog and human testes. To determine the physiological importance of the Wnt pathway, we developed a mouse model with germ cell-specific constitutive activation of ßcatenin. In young mutants, similar to controls, germ cell development was normal. However, with age, mutant testes showed defective spermatogenesis, progressive germ cell loss, and flawed meiotic entry of spermatogonial cells. Flow sorting confirmed reduced germ cell populations at the leptotene/zygotene stages of meiosis in mutant group. Using thymidine analogues-based DNA double labelling technique, we further established decline in germ cell proliferation and differentiation. Overactivation of Wnt/ßcatenin signalling in a spermatogonial cell line resulted in reduced cell proliferation, viability and colony formation. RNA sequencing analysis of testes revealed significant alterations in the non-coding regions of mutant mouse genome. One of the novel non-coding RNAs was switched on in mutant testes compared to controls. QPCR analysis confirmed upregulation of this unique noncoding RNA in mutant testis. In summary, our results highlight the significance of Wnt signalling in male germ cells.
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Nova |
2016 |
Zhang X, Gee H, Rose B, Lee CS, Clark J, Elliott M, et al., 'Regulation of the tumour suppressor PDCD4 by miR-499 and miR-21 in oropharyngeal cancers', BMC Cancer, 16 (2016) [C1]
Background: The rates of oropharyngeal cancers such as tonsil cancers are increasing. The tumour suppressor protein Programmed Cell Death Protein 4 (PDCD4) has been implicated in ... [more]
Background: The rates of oropharyngeal cancers such as tonsil cancers are increasing. The tumour suppressor protein Programmed Cell Death Protein 4 (PDCD4) has been implicated in the development of various human cancers and small RNAs such as microRNAs (miRNAs) can regulate its expression. However the exact regulation of PDCD4 by multiple miRNAs in oropharyngeal squamous cell carcinoma (SCC) is not well understood. Results: Using two independent oropharyngeal SCC cohorts with a focus on the tonsillar region, we identified a miRNA profile differentiating SCC tissue from normal. Both miR-21 and miR-499 were highly expressed in tonsil SCC tissues displaying a loss of PDCD4. Interestingly, expression of the miRNA machinery, Dicer1, Drosha, DDX5 (Dead Box Helicase 5) and DGCR8 (DiGeorge Syndrome Critical Region Gene 8) were all elevated by greater than 2 fold in the tonsil SCC tissue. The 3'UTR of PDCD4 contains three binding-sites for miR-499 and one for miR-21. Using a wild-type and truncated 3'UTR of PDCD4, we demonstrated that the initial suppression of PDCD4 was mediated by miR-21 whilst sustained suppression was mediated by miR-499. Moreover the single miR-21 site was able to elicit the same magnitude of suppression as the three miR-499 sites. Conclusion: This study describes the regulation of PDCD4 specifically in tonsil SCC by miR-499 and miR-21 and has documented the loss of PDCD4 in tonsil SCCs. These findings highlight the complex interplay between miRNAs and tumour suppressor gene regulation and suggest that PDCD4 loss may be an important step in tonsillar carcinogenesis.
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Nova |
2016 |
Giacomotto J, Carroll AP, Rinkwitz S, Mowry B, Cairns MJ, Becker TS, 'Developmental suppression of schizophrenia-associated miR-137 alters sensorimotor function in zebrafish.', Translational psychiatry, 6 e818 (2016) [C1]
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Nova |
2016 |
Hollins SL, Zavitsanou K, Walker FR, Cairns MJ, 'Alteration of transcriptional networks in the entorhinal cortex after maternal immune activation and adolescent cannabinoid exposure', Brain, Behavior, and Immunity, 56 187-196 (2016) [C1]
Maternal immune activation (MIA) and adolescent cannabinoid exposure (ACE) have both been identified as major environmental risk factors for schizophrenia. We examined the effects... [more]
Maternal immune activation (MIA) and adolescent cannabinoid exposure (ACE) have both been identified as major environmental risk factors for schizophrenia. We examined the effects of these two risk factors alone, and in combination, on gene expression during late adolescence. Pregnant rats were exposed to the viral infection mimic polyriboinosinic-polyribocytidylic acid (poly I:C) on gestational day (GD) 15. Adolescent offspring received daily injections of the cannabinoid HU210 for 14 days starting on postnatal day (PND) 35. Gene expression was examined in the left entorhinal cortex (EC) using mRNA microarrays. We found prenatal treatment with poly I:C alone, or HU210 alone, produced relatively minor changes in gene expression. However, following combined treatments, offspring displayed significant changes in transcription. This dramatic and persistent alteration of transcriptional networks enriched with genes involved in neurotransmission, cellular signalling and schizophrenia, was associated with a corresponding perturbation in the expression of small non-coding microRNA (miRNA). These results suggest that a combination of environmental exposures during development leads to significant genomic remodeling that disrupts maturation of the EC and its associated circuitry with important implications as the potential antecedents of memory and learning deficits in schizophrenia and other neuropsychiatric disorders.
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2016 |
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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2016 |
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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2016 |
Pouget JG, Gonçalves VF, Spain SL, Finucane HK, Raychaudhuri S, Kennedy JL, Knight J, 'Genome-Wide Association Studies Suggest Limited Immune Gene Enrichment in Schizophrenia Compared to 5 Autoimmune Diseases', Schizophrenia Bulletin, 42 1176-1184 (2016) [C1]
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2016 |
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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2016 |
Holland D, Wang Y, Thompson WK, Schork A, Chen C-H, Lo M-T, et al., 'Estimating Effect Sizes and Expected Replication Probabilities from GWAS Summary Statistics', Frontiers in Genetics, 7 (2016) [C1]
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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 |
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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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 |
Hollins SL, Cairns MJ, 'MicroRNA: Small RNA mediators of the brains genomic response to environmental stress', Progress in Neurobiology, 143 61-81 (2016) [C1]
The developmental processes that establish the synaptic architecture of the brain while retaining capacity for activity-dependent remodeling, are complex and involve a combination... [more]
The developmental processes that establish the synaptic architecture of the brain while retaining capacity for activity-dependent remodeling, are complex and involve a combination of genetic and epigenetic influences. Dysregulation of these processes can lead to problems with neural circuitry which manifest in humans as a range of neurodevelopmental syndromes, such as schizophrenia, bipolar disorder and fragile X mental retardation. Recent studies suggest that prenatal, postnatal and intergenerational environmental factors play an important role in the aetiology of stress-related psychopathology. A number of these disorders have been shown to display epigenetic changes in the postmortem brain that reflect early life experience. These changes affect the regulation of gene expression though chromatin remodeling (transcriptional) and post-transcriptional influences, especially small noncoding microRNA (miRNA). These dynamic and influential molecules appear to play an important function in both brain development and its adaption to stress. In this review, we examine the role of miRNA in mediating the brain's response to both prenatal and postnatal environmental perturbations and explore how stress- induced alterations in miRNA expression can regulate the stress response via modulation of the immune system. Given the close relationship between environmental stress, miRNA, and brain development/function, we assert that miRNA hold a significant position at the molecular crossroads between neural development and adaptations to environmental stress. A greater understanding of the dynamics that mediate an individual's predisposition to stress-induced neuropathology has major human health benefits and is an important area of research.
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2016 |
Prins BP, Abbasi A, Wong A, Vaez A, Nolte I, Franceschini N, et al., 'Investigating the Causal Relationship of C-Reactive Protein with 32 Complex Somatic and Psychiatric Outcomes: A Large-Scale Cross-Consortium Mendelian Randomization Study', PLOS Medicine, 13 e1001976-e1001976 (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 |
Carrick WT, Burks B, Cairns MJ, Kocerha J, 'Noncoding RNA Regulation of Dopamine Signaling in Diseases of the Central Nervous System.', Front Mol Biosci, 3 (2016) [C1]
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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 |
Cairns MJ, 'Circulating miRNA biomarkers for schizophrenia?', American Journal of Psychiatry, 172 1059-1061 (2015) [C3]
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2015 |
Quinn RK, Brown AL, Goldie BJ, Levi EM, Dickson PW, Smith DW, et al., 'Distinct miRNA expression in dorsal striatal subregions is associated with risk for addiction in rats', Translational Psychiatry, 5 (2015) [C1]
Recently, we published data using an animal model that allowed us to characterize animals into two groups, addiction vulnerable and addiction resilient, where we identified that a... [more]
Recently, we published data using an animal model that allowed us to characterize animals into two groups, addiction vulnerable and addiction resilient, where we identified that addiction/relapse vulnerability was associated with deficits in synaptic plasticityassociated gene expression in the dorsal striatum (DS). Notable was the strong reduction in expression for activity-regulated cytoskeleton-associated protein (Arc) considered a master regulator of synaptic plasticity. In the present study, we confirmed that Arc messenger RNA was significantly decreased in the DS, but importantly, we identified that this reduction was restricted to the dorsomedial (DMS) and not dorsolateral striatum (DLS). There is recent evidence of microRNA (miRNA)-associated posttranscriptional suppression of Arc and animal models of addiction have identified a key role for miRNA in the regulation of addiction-relevant genes. In further support of this link, we identified several differentially expressed miRNA with the potential to influence addiction-relevant plasticity genes, including Arc. A key study recently reported that miR-212 expression is protective against compulsive cocaine-seeking. Supporting this hypothesis, we found that miR-212 expression was significantly reduced in the DMS but not DLS of addiction-vulnerable animals. Together, our data provide strong evidence that miRNA promote ongoing plasticity deficits in the DS of addiction-vulnerable animals.
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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 |
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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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 |
Geaghan M, Cairns MJ, 'MicroRNA and Posttranscriptional Dysregulation in Psychiatry', Biological Psychiatry, 78 231-239 (2015) [C1]
Psychiatric syndromes, including schizophrenia, mood disorders, and autism spectrum disorders, are characterized by a complex range of symptoms, including psychosis, depression, m... [more]
Psychiatric syndromes, including schizophrenia, mood disorders, and autism spectrum disorders, are characterized by a complex range of symptoms, including psychosis, depression, mania, and cognitive deficits. Although the mechanisms driving pathophysiology are complex and remain largely unknown, advances in the understanding of gene association and gene networks are providing significant clues to their etiology. In recent years, small noncoding RNA molecules known as microRNA (miRNA) have emerged as potential players in the pathophysiology of mental illness. These small RNAs regulate hundreds of target transcripts by modifying their stability and translation on a broad scale, influencing entire gene networks in the process. There is evidence to suggest that numerous miRNAs are dysregulated in postmortem neuropathology of neuropsychiatric disorders, and there is strong genetic support for association of miRNA genes and their targets with these conditions. This review presents the accumulated evidence linking miRNA dysregulation and dysfunction with schizophrenia, bipolar disorder, major depressive disorder, and autism spectrum disorders and the potential of miRNAs as biomarkers or therapeutics for these disorders. We further assess the functional roles of some outstanding miRNAs associated with these conditions and how they may be influencing the development of psychiatric symptoms.
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2015 |
Wang X, Gardiner EJ, Cairns MJ, 'Optimal consistency in microRNA expression analysis using reference-gene-based normalization', MOLECULAR BIOSYSTEMS, 11 1235-1240 (2015) [C1]
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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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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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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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2014 |
Goldie BJ, Dun MD, Lin M, Smith ND, Verrills NM, Dayas CV, Cairns MJ, 'Activity-associated miRNA are packaged in Map1b-enriched exosomes released from depolarized neurons.', Nucleic Acids Research, 42 9195-9208 (2014) [C1]
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2014 |
Yu X, Yang L, Cairns MJ, Dass C, Saravolac E, Li X, Sun LQ, 'Chemosensitization of solid tumors by inhibition of Bcl-xL expression using DNAzyme', Oncotarget, 5 9039-9048 (2014) [C1]
DNAzymes are a novel class of gene suppressors that selectively bind to an RNA substrate by Watson-Crick base pairing and cleave phosphodiester bonds. To explore the potential for... [more]
DNAzymes are a novel class of gene suppressors that selectively bind to an RNA substrate by Watson-Crick base pairing and cleave phosphodiester bonds. To explore the potential for therapeutic use of catalytic DNA molecules, active DNAzymes targeting the bcl-xL gene were generated through a multiplex in vitro selection. The DNAzyme-mediated down-regulation of the bcl-xL expression was demonstrated in various cancer cell lines by Western blots. Treatment of the cells with the active DNAzyme led to increases in percentage of apoptotic cells and cytochrome c release from mitochondria, a hall marker of apoptosis. When combined with chemotherapeutics such as Taxol, the DNAzyme significantly sensitised a panel of cancer cells to apoptosis as measured by cell survival assay. In Taxol-resistant cells, down-regulation of bcl-xL expression by the DNAzyme reversed the chemo-resistant phenotype of the cancer cells. In a xenograft mouse model, the DNAzyme was delivered into the tumors via an ALZET osmotic pump and shown to chemosensitize PC3 tumor when treating with Taxol. The results from the present study demonstrate that bcl-xL DNAzyme treatment facilitates apoptosis in solid tumors and suggest the potential use of bcl-xL DNAzyme in combination with chemotherapeutics for cancer therapy.
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2014 |
Gupta P, Cairns MJ, Saksena NK, 'Regulation of gene expression by microRNA in HCV infection and HCV-mediated hepatocellular carcinoma', Virology Journal, 11 (2014) [C1]
MicroRNA (miRNA) exert a profound effect on Hepatitis C virus (HCV) replication and on the manifestation of HCV-associated hepatocellular carcinoma (HCC). miR-122 in particular, i... [more]
MicroRNA (miRNA) exert a profound effect on Hepatitis C virus (HCV) replication and on the manifestation of HCV-associated hepatocellular carcinoma (HCC). miR-122 in particular, is highly enriched in liver and has been shown to interact with HCV, suggesting this virus has evolved to subvert and manipulate the host gene silencing machinery in order to support its life cycle. It is therefore likely that miR-122 and other miRNAs play an important role in the pathophysiology of HCV infection. The changes in post-transcriptional gene regulation by the miRNAs may play a key role in the manifestation of chronic liver disease and hepatocellular carcinoma. Understanding of HCV-host miRNA interactions will ultimately lead to the design of therapeutic modalities against HCV infection and HCV-mediated HCC and may also provide important biomarkers that direct treatment options. Here, we review the current knowledge on the role of miRNA and gene expression on HCV infection and hepatocellular carcinoma, in addition to the possible role of miRNA as future therapeutic targets. © 2014 Gupta et al.; licensee BioMed Central Ltd.
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2014 |
Gould IC, Shepherd AM, Laurens KR, Cairns MJ, Carr VJ, Green MJ, 'Multivariate neuroanatomical classification of cognitive subtypes in schizophrenia: A support vector machine learning approach', NeuroImage: Clinical, 6 229-236 (2014) [C1]
Heterogeneity in the structural brain abnormalities associated with schizophrenia has made identification of reliable neuroanatomical markers of the disease difficult. The use of ... [more]
Heterogeneity in the structural brain abnormalities associated with schizophrenia has made identification of reliable neuroanatomical markers of the disease difficult. The use of more homogenous clinical phenotypes may improve the accuracy of predicting psychotic disorder/s on the basis of observable brain disturbances. Here we investigate the utility of cognitive subtypes of schizophrenia-'cognitive deficit' and 'cognitively spared'-in determining whether multivariate patterns of volumetric brain differences can accurately discriminate these clinical subtypes from healthy controls, and from each other. We applied support vector machine classification to grey-and white-matter volume data from 126 schizophrenia patients previously allocated to the cognitive spared subtype, 74 cognitive deficit schizophrenia patients, and 134 healthy controls. Using this method, cognitive subtypes were distinguished from healthy controls with up to 72% accuracy. Cross-validation analyses between subtypes achieved an accuracy of 71%, suggesting that some common neuroanatomical patterns distinguish both subtypes from healthy controls. Notably, cognitive subtypes were best distinguished from one another when the sample was stratified by sex prior to classification analysis: cognitive subtype classification accuracy was relatively low (<60%) without stratification, and increased to 83% for females with sex stratification. Distinct neuroanatomical patterns predicted cognitive subtype status in each sex: sex-specific multivariate patterns did not predict cognitive subtype status in the other sex above chance, and weight map analyses demonstrated negative correlations between the spatial patterns of weights underlying classification for each sex. These results suggest that in typical mixed-sex samples of schizophrenia patients, the volumetric brain differences between cognitive subtypes are relatively minor in contrast to the large common disease-associated changes. Volumetric differences that distinguish between cognitive subtypes on a case-by-case basis appear to occur in a sex-specific manner that is consistent with previous evidence of disrupted relationships between brain structure and cognition in male, but not female, schizophrenia patients. Consideration of sex-specific differences in brain organization is thus likely to assist future attempts to distinguish subgroups of schizophrenia patients on the basis of neuroanatomical features.
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2014 |
McCarthy-Jones S, Green MJ, Scott RJ, Tooney PA, Cairns MJ, Wu JQ, et al., 'Preliminary evidence of an interaction between the FOXP2 gene and childhood emotional abuse predicting likelihood of auditory verbal hallucinations in schizophrenia', JOURNAL OF PSYCHIATRIC RESEARCH, 50 66-72 (2014) [C1]
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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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2014 |
Gupta P, Liu B, Wu JQ, Soriano V, Vispo E, Carroll AP, et al., 'Genome-wide mRNA and miRNA analysis of peripheral blood mononuclear cells (PBMC) reveals different miRNAs regulating HIV/HCV co-infection', Virology, 450-451 336-349 (2014) [C1]
Co-infection with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) is common due to shared transmission routes. The genomic basis of HIV/HCV co-infection and its reg... [more]
Co-infection with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) is common due to shared transmission routes. The genomic basis of HIV/HCV co-infection and its regulation by microRNA (miRNA) is unknown. Therefore, our objective was to investigate genome-wide mRNA expression and its regulation by miRNA in primary PBMCs derived from 27 patients (5 HCV - mono-infected, 5 HIV-mono-infected, 12 HCV/HIV co-infected, and 5 healthy controls). This revealed 27 miRNAs and 476 mRNAs as differentially expressed (DE) in HCV/HIV co-infection when compared to controls (adj p<0.05). Our study shows the first evidence of miRNAs specific for co-infection, several of which are correlated with key gene targets demonstrating functional relationships to pathways in cancer, immune-function, and metabolism. Notable was the up regulation of HCV-specific miR-122 in co-infection (FC>50, p=4.02E-06), which may have clinical/biological implications. © 2013 Elsevier Inc.
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2014 |
Wang X, Cairns MJ, 'Understanding complex transcriptome dynamics in schizophrenia and other neurological diseases using RNA sequencing 127-152 (2014) [C1]
How the human brain develops and adapts with its trillions of functionally integrated synapses remains one of the greatest mysteries of life. With tremendous advances in neuroscie... [more]
How the human brain develops and adapts with its trillions of functionally integrated synapses remains one of the greatest mysteries of life. With tremendous advances in neuroscience, genetics, and molecular biology, we are beginning to appreciate the scope of this complexity and define some of the parameters of the systems that make it possible. These same tools are also leading to advances in our understanding of the pathophysiology of neurocognitive and neuropsychiatric disorders. Like the substrate for these problems, the etiology is usually complex-involving an array of genetic and environmental influences. To resolve these influences and derive better interventions, we need to reveal every aspect of this complexity and model their interactions and define the systems and their regulatory structure. This is particularly important at the tissue-specific molecular interface between the underlying genetic and environmental influence defined by the transcriptome. Recent advances in transcriptome analysis facilitated by RNA sequencing (RNA-Seq) can provide unprecedented insight into the functional genomics of neurological disorders. In this review, we outline the advantages of this approach and highlight some early application of this technology in the investigation of the neuropathology of schizophrenia. Recent progress of RNA-Seq studies in schizophrenia has shown that there is extraordinary transcriptome dynamics with significant levels of alternative splicing. These studies only scratch the surface of this complexity and therefore future studies with greater depth and samples size will be vital to fully explore transcriptional diversity and its underlying influences in schizophrenia and provide the basis for new biomarkers and improved treatments. © 2014 Elsevier Inc.
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2014 |
Walker FR, Beynon SB, Jones KA, Zhao Z, Kongsui R, Cairns M, Nilsson M, 'Dynamic structural remodelling of microglia in health and disease: A review of the models, the signals and the mechanisms', BRAIN BEHAVIOR AND IMMUNITY, 37 1-14 (2014) [C1]
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2014 |
Barry G, Briggs JA, Vanichkina DP, Poth EM, Beveridge NJ, Ratnu VS, et al., 'The long non-coding RNA Gomafu is acutely regulated in response to neuronal activation and involved in schizophrenia-associated alternative splicing', Molecular Psychiatry, 19 486-494 (2014) [C1]
Schizophrenia (SZ) is a complex disease characterized by impaired neuronal functioning. Although defective alternative splicing has been linked to SZ, the molecular mechanisms res... [more]
Schizophrenia (SZ) is a complex disease characterized by impaired neuronal functioning. Although defective alternative splicing has been linked to SZ, the molecular mechanisms responsible are unknown. Additionally, there is limited understanding of the early transcriptomic responses to neuronal activation. Here, we profile these transcriptomic responses and show that long non-coding RNAs (lncRNAs) are dynamically regulated by neuronal activation, including acute downregulation of the lncRNA Gomafu, previously implicated in brain and retinal development. Moreover, we demonstrate that Gomafu binds directly to the splicing factors QKI and SRSF1 (serine/arginine-rich splicing factor 1) and dysregulation of Gomafu leads to alternative splicing patterns that resemble those observed in SZ for the archetypal SZ-associated genes DISC1 and ERBB4. Finally, we show that Gomafu is downregulated in post-mortem cortical gray matter from the superior temporal gyrus in SZ. These results functionally link activity-regulated lncRNAs and alternative splicing in neuronal function and suggest that their dysregulation may contribute to neurological disorders. © 2014 Macmillan Publishers Limited.
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2014 |
Hollins SL, Goldie BJ, Carroll AP, Mason EA, Walker FR, Eyles DW, Cairns MJ, 'Ontogeny of small RNA in the regulation of mammalian brain development', BMC GENOMICS, 15 (2014) [C1]
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2014 |
Gardiner E, Carroll A, Tooney PA, Cairns MJ, 'Antipsychotic drug-associated gene-miRNA interaction in T-lymphocytes', International Journal of Neuropsychopharmacology, 17 929-943 (2014) [C1]
Antipsychotic drugs (APDs) can have a profound effect on the human body that extends well beyond our understanding of their neuropsychopharmacology. Some of these effects manifest... [more]
Antipsychotic drugs (APDs) can have a profound effect on the human body that extends well beyond our understanding of their neuropsychopharmacology. Some of these effects manifest themselves in peripheral blood lymphocytes, and in some cases, particularly in clozapine treatment, result in serious complications. To better understand the molecular biology of APD action in lymphocytes, we investigated the influence of chlorpromazine, haloperidol and clozapine in vitro, by microarray-based gene and microRNA (miRNA) expression analysis. JM-Jurkat T-lymphocytes were cultured in the presence of the APDs or vehicle alone over 2 wk to model the early effects of APDs on expression. Interestingly both haloperidol and clozapine appear to regulate the expression of a large number of genes. Functional analysis of APD-associated differential expression revealed changes in genes related to oxidative stress, metabolic disease and surprisingly also implicated pathways and biological processes associated with neurological disease consistent with current understanding of the activity of APDs. We also identified miRNA-mRNA interaction associated with metabolic pathways and cell death/survival, all which could have relevance to known side effects of APDs. These results indicate that APDs have a significant effect on expression in peripheral tissue that relate to both known mechanisms as well as poorly characterized side effects. © CINP 2014.
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2014 |
Liu B, Li J, Cairns MJ, 'Identifying miRNAs, targets and functions', Briefings in Bioinformatics, 15 1-19 (2014) [C1]
MicroRNAs (miRNAs) are small endogenous non-coding RNAs that function as the universal specificity factors in post-transcriptional gene silencing. Discovering miRNAs, identifying ... [more]
MicroRNAs (miRNAs) are small endogenous non-coding RNAs that function as the universal specificity factors in post-transcriptional gene silencing. Discovering miRNAs, identifying their targets and further inferring miRNA functions have been a critical strategy for understanding normal biological processes of miRNAs and their roles in the development of disease. In this review, we focus on computationalmethods of inferringmiRNA functions, including miRNA functional annotation and inferring miRNA regulatory modules, by integrating heterogeneous data sources.We also briefly introduce the research in miRNA discovery and miRNA-target identification with an emphasis on the challenges to computational biology. © The Author 2012. Published by Oxford University Press.
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2014 |
Hollins SL, Zavitsanou K, Walker FR, Cairns MJ, 'Alteration of imprinted Dlk1-Dio3 miRNA cluster expression in the entorhinal cortex induced by maternal immune activation and adolescent cannabinoid exposure.', Transl Psychiatry, 4 e452 (2014) [C1]
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2014 |
Hollins SL, Cairns MJ, Zavitsanou K, Walker FR, '5:15 PM INTERACTION OF MATERNAL INFECTION AND ADOLESCENT CANNABINOID EXPOSURE ON MIRNA REGULATION OF GENE EXPRESSION IN THE ADULT ENTORHINAL CORTEX', Schizophrenia Research, 153 S61-S61 (2014)
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2014 |
Atkins JR, Wu JQ, Tooney PA, Scott RJ, Carr VJ, Cairns MJ, 'Poster #S132 COPY NUMBER VARIANT ANALYSIS ON 401 CASES OF SCHIZOPHRENIA: A SEARCH FOR CAUSAL GENES FINDS DISRUPTION IN THE NEUROGENESIS REGULATOR JAGGED 2', Schizophrenia Research, 153 S136-S136 (2014)
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2014 |
Raudino A, Carr VJ, Cairns MJ, Oldmeadow C, Tooney PA, Scott RJ, Green MJ, 'Poster #S143 INTERACTIVE EFFECTS OF FKBP5 AND CHILDHOOD TRAUMA ON COGNITION IN SCHIZOPHRENIA', Schizophrenia Research, 153 S140-S141 (2014)
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2014 |
Wu JQ, Green MJ, Gardiner E, Tooney P, Scott RJ, Carr VJ, Cairns MJ, 'Poster #M102 TRANSCRIPTOME ANALYSIS REVEALS DOWN-REGULATED SIGNAL TRANSDUCTION PATHWAYS IN PERIPHERAL BLOOD MONONUCLEAR CELLS FROM SCHIZOPHRENIA PATIENTS WITH COGNITIVE IMPAIRMENT', Schizophrenia Research, 153 S226-S227 (2014)
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2014 |
Cairns MJ, Wang X, Atkins JR, Fillman SG, Tooney P, Scott RJ, et al., 'Poster #M175 GENE SET ENRICHMENT OF DIFFERENTIAL EXPRESSION AND SPLICING ANALYSIS BY RNA-SEQ IN POSTMORTEM DLPFC AND PBMCS IN SCHIZOPHRENIA', Schizophrenia Research, 153 S254-S254 (2014)
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2014 |
Goldie BJ, Barnett MM, Cairns MJ, 'BDNF and the maturation of posttranscriptional regulatory networks in human SH-SY5Y neuroblast differentiation', Frontiers in Cellular Neuroscience, 8 (2014) [C1]
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2014 |
Wang X, Cairns MJ, 'SeqGSEA: A Bioconductor package for gene set enrichment analysis of RNA-Seq data integrating differential expression and splicing', Bioinformatics, 30 1777-1779 (2014) [C3]
SeqGSEA is an open-source Bioconductor package for the functional integration of differential expression and splicing analysis in RNA-Seq data. SeqGSEA implements an analysis pipe... [more]
SeqGSEA is an open-source Bioconductor package for the functional integration of differential expression and splicing analysis in RNA-Seq data. SeqGSEA implements an analysis pipeline, which first computes differential splicing and differential expression scores, followed by integrating them into a per-gene score that quantifies each gene's association with a phenotype of interest, and finally executes gene set enrichment analysis in a cutoff-free manner to achieve biological insights. SeqGSEA accounts for biological variability and determines the statistical significance of gene pathways and networks using subject permutation, and thus requires at least five samples per group. Real applications show that SeqGSEA detects more biologically meaningful gene sets without biases toward long or highly expressed genes. SeqGSEA can be set up to run in parallel to reduce the analysis time. © 2014 The Author. Published by Oxford University Press. All rights reserved.
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2013 |
Cairns MJ, Kocerha J, 'Advances in non-coding RNA profiling for neurological diseases', Frontiers in Genetics, 4 (2013) [C3]
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2013 |
Liu B, Liu L, Tsykin A, Goodall GJ, Cairns MJ, Li J, 'Discovering functional microRNAmRNA regulatory modules in heterogeneous data', Advances in Experimental Medicine and Biology, 774 267-290 (2013)
microRNAs (miRNAs) are small non-coding RNAs that cause mRNA degradation and translation inhibition. They are pivotal regulators of development and cellular homeostasis through th... [more]
microRNAs (miRNAs) are small non-coding RNAs that cause mRNA degradation and translation inhibition. They are pivotal regulators of development and cellular homeostasis through their control of diverse processes. Recently, great efforts have been made to elucidate many targets that are affected by miRNAs, but the functions of most miRNAs and their precise regulatory mechanisms remain elusive. With more and more matched expression profiles of miRNAs and mRNAs having been made available, it is of great interest to utilize both expression profiles and sequence information to discover the functional regulatory networks of miRNAs and their target mRNAs for potential biological processes that they may participate in. In this chapter, we first brie fly review the computational methods for discovering miRNA targets and miRNA-mRNA regulatory modules, and then focus on a method of identifying functional miRNA-mRNA regulatory modules by integrating multiple data sets from different sources. © Springer Science+Business Media Dordrecht 2013.
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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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2013 |
Santarelli DM, Liu B, Duncan CE, Beveridge NJ, Tooney PA, Schofield PR, Cairns MJ, 'Gene-microRNA interactions associated with antipsychotic mechanisms and the metabolic side effects of olanzapine', PSYCHOPHARMACOLOGY, 227 67-78 (2013) [C1]
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2013 |
Wong J, Duncan CE, Beveridge NJ, Webster MJ, Cairns MJ, Weickert CS, 'Expression of NPAS3 in the Human Cortex and Evidence of Its Posttranscriptional Regulation by miR-17 During Development, With Implications for Schizophrenia', SCHIZOPHRENIA BULLETIN, 39 396-406 (2013) [C1]
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2013 |
Fillman SG, Cloonan N, Catts VS, Miller LC, Wong J, McCrossin T, et al., 'Increased inflammatory markers identified in the dorsolateral prefrontal cortex of individuals with schizophrenia', MOLECULAR PSYCHIATRY, 18 206-214 (2013) [C1]
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2013 |
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, 18 774-780 (2013) [C1]
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2013 |
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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2013 |
Bond DR, Cairns M, Ashman LK, Weidenhofer J, 'Abstract 5283: Regulation of tetraspanins CD151 and CD9 by micro-RNA in breast and prostate cancers.', Cancer Research, 73 5283-5283 (2013)
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2013 |
Wang X, Cairns MJ, 'Gene set enrichment analysis of RNA-Seq data: integrating differential expression and splicing', BMC BIOINFORMATICS, 14 (2013) [C1]
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2013 |
Carroll AP, Tooney PA, Cairns MJ, 'Context-specific microRNA function in developmental complexity', Journal of Molecular Cell Biology, 5 73-84 (2013) [C1]
Since their discovery, microRNAs (miRNA) have been implicated in a vast array of biological processes in animals, from fundamental developmental functions including cellular proli... [more]
Since their discovery, microRNAs (miRNA) have been implicated in a vast array of biological processes in animals, from fundamental developmental functions including cellular proliferation and differentiation, to more complex and specialized roles such as long-term potentiation and synapse-specific modifications in neurons. This review recounts the history behind this paradigm shift, which has seen small non-coding RNA molecules coming to the forefront of molecular biology, and introduces their role in establishing developmental complexity in animals. The fundamental mechanisms of miRNA biogenesis and function are then considered, leading into a discussion of recent discoveries transforming our understanding of how these molecules regulate gene network behaviour throughout developmental and pathophysiological processes. The emerging complexity of this mechanism is also examined with respect to the influence of cellular context on miRNA function. This discussion highlights the absolute imperative for experimental designs to appreciate the significance of context-specific factors when determining what genes are regulated by a particular miRNA. Moreover, by establishing the timing, location, and mechanism of these regulatory events, we may ultimately understand the true biological function of a specific miRNA in a given cellular environment. © The Author (2013).
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2013 |
Carroll AP, Tooney PA, Cairns MJ, 'Design and interpretation of microRNA-reporter gene activity.', Analytical biochemistry, 437 164-171 (2013) [C1]
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2013 |
Scarr E, Craig JM, Cairns MJ, Seo MS, Galati JC, Beveridge NJ, et al., 'Decreased cortical muscarinic M1 receptors in schizophrenia are associated with changes in gene promoter methylation, mRNA and gene targeting microRNA', TRANSLATIONAL PSYCHIATRY, 3 (2013) [C1]
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Nova |
2012 |
Tynan R, Weidenhofer JC, Hinwood M, Cairns MJ, Day TA, Walker FR, 'A comparative examination of the anti-inflammatory effects of SSRI and SNRI antidepressants on LPS stimulated microglia', Brain Behavior and Immunity, 26 469-479 (2012) [C1]
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2012 |
Cairns M, 'MICRORNA BIOMARKERS OF SCHIZOPHRENIA IN BLOOD', SCHIZOPHRENIA RESEARCH, 136 S54-S54 (2012)
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2012 |
Goldie BJ, Cairns MJ, 'Post-transcriptional trafficking and regulation of neuronal gene expression', Molecular Neurobiology, 45 99-108 (2012) [C1]
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2012 |
Beveridge NJ, Cairns MJ, 'MicroRNA dysregulation in schizophrenia', Neurobiology of Disease, 46 263-271 (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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2012 |
Green MJ, Chia T-Y, Cairns MJ, Wu JQ, Tooney P, Scott RJ, Carr VI, 'Poster #102 COMT GENOTYPE MODULATES THE EFFECTS OF CHILDHOOD ADVERSITY ON COGNITION AND SYMPTOMS IN SCHIZOPHRENIA', Schizophrenia Research, 136 S222-S222 (2012)
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2012 |
Gardiner EJ, Cairns MJ, Beveridge NJ, Liu B, Carr V, Scott R, Tooney P, 'Poster #112 IMMUNE-RELATED DIFFERENTIAL EXPRESSION PROFILE IN PERIPHERAL BLOOD MONONUCLEAR CELLS IN SCHIZOPHRENIA', Schizophrenia Research, 136 S225-S226 (2012)
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2012 |
Green MI, Chia T-Y, Cairns MJ, Tooney P, Scott RJ, Carr VJ, 'Poster #113 COMT MODULATES THE EFFECTS OF LIFETIME CANNABIS USE ON COGNITION AND SYMPTOM PROFILES IN SCHIZOPHRENIA', Schizophrenia Research, 136 S226-S226 (2012)
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2012 |
Green MI, Cairns MJ, Wu JQ, Dragovic M, Jablensky A, Tooney P, et al., 'Poster #114 GENOME-WIDE SUPPORTED VARIANTS (MIR137) PREDICTS MEMBERSHIP OF A COGNITIVE SUBTYPE OF SCHIZOPHRENIA', Schizophrenia Research, 136 S226-S226 (2012)
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2012 |
Carroll AP, Tran N, Tooney PA, Cairns MJ, 'Alternative mRNA fates identified in microRNA-associated transcriptome analysis', BMC Genomics, 13 1-19 (2012) [C1]
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Nova |
2012 |
Zhou L, Pupo GM, Gupta P, Liu B, Tran SL, Rahme R, et al., 'A parallel genome-wide mRNA and microRNA profiling of the frontal cortex of HIV patients with and without HIV-associated dementia shows the role of axon guidance and downstream pathways in HIV-mediated neurodegeneration', BMC Genomics, 13 (2012) [C1]
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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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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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2011 |
Santarelli DMF, Beveridge NJ, Tooney PA, Cairns MJ, 'Upregulation of dicer and MicroRNA expression in the dorsolateral prefrontal cortex Brodmann area 46 in schizophrenia', Biological Psychiatry, 69 180-187 (2011) [C1]
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2010 |
Saravolac EG, Wong JP, Cairns MJ, 'Recent patents in antiviral siRNAs', Recent Patents on Anti-Infective Drug Discovery, 5 44-57 (2010) [C1]
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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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2010 |
Carland M, Grannas MJ, Cairns MJ, Roknic V, Denny WA, McFadyen WD, Murray V, 'Substituted 9-aminoacridine-4-carboxamides tethered to platinum(II)diamine complexes: Chemistry, cytotoxicity and DNA sequence selectivity', Journal of Inorganic Biochemistry, 104 815-819 (2010) [C1]
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2010 |
Wong JP, Christopher ME, Salazar AM, Sun L-Q, Viswanathan S, Wang M, et al., 'Broad-spectrum and virus-specific nucleic acid-based antivirals against influenza', Frontiers in Bioscience, 1 791-800 (2010) [C1]
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2010 |
Beveridge NJ, Gardiner EJ, Carroll AP, Tooney PA, Cairns MJ, 'Schizophrenia is associated with an increase in cortical microRNA biogenesis', Molecular Psychiatry, 15 1176-1189 (2010) [C1]
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2009 |
Cairns MJ, Thomas T, Beltran CE, Tillett D, 'Primer fabrication using polymerase mediated oligonucleotide synthesis', BMC Genomics, 10 1-10 (2009) [C1]
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Nova |
2009 |
Zhang X, Cairns MJ, Rose B, O'Brien C, Shannon K, Clark J, et al., 'Alterations in miRNA processing and expression in pleomorphic adenomas of the salivary gland', International Journal of Cancer, 124 2855-2863 (2009) [C1]
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2009 |
Lai A, Cairns MJ, Tran N, Zhang H-P, Cullen L, Arndt GM, 'RNA modulators of complex phenotypes in mammalian cells', PLoS ONE, 4 e4758 (2009) [C1]
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2009 |
Cairns MJ, Carland M, David Mcfadyen W, Denny WA, Murray V, 'The DNA sequence selectivity of maltolato-containing cisplatin analogues in purified plasmid DNA and in intact human cells', Journal of Inorganic Biochemistry, 103 1151-1155 (2009) [C1]
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2009 |
Beveridge NJ, Tooney PA, Carroll AP, Tran N, Cairns MJ, 'Down-regulation of miR-17 family expression in response to retinoic acid induced neuronal differentiation', Cellular Signalling, 21 1837-1845 (2009) [C1]
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2008 |
Cairns MJ, 'Small interfering RNAs and their therapeutic applications in mitigation of virus replication and pathological effects in the respiratory tract', Anti-Inflammatory and Anti-Allergy Agents in Medicinal Chemistry, 7 116-121 (2008) [C1]
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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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2007 |
Wong JP, Christopher ME, Cairns M, Sun LQ, Dale RMK, Salazar AM, 'Current Status on Development of Nucleic Acid-Based Antiviral Drugs Against Influenza Virus Infection 126-147 (2007)
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2007 |
Bhindi R, Fahmy RG, Lowe HC, Chesterman CN, Dass CR, Cairns MJ, et al., 'Brothers in arms: DNA enzymes, short interfering RNA, and the emerging wave of small-molecule nucleic acid-based gene-silencing strategies', American Journal of Pathology, 171 1079-1088 (2007) [C1]
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2004 |
Cairns MJ, Turner R, Sun L-Q, 'Homogeneous real-time detection and quantification of nucleic acid amplification using restriction enzyme digestion', Biochemical and Biophysical Research Communications, 318 684-690 (2004) [C1]
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2003 |
Tran N, Cairns MJ, Dawes IW, Arndt GM, 'Expressing functional siRNAs in mammalian cells using convergent transcription', BMC Biotechnology, 3 0-0 (2003) [C1]
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2003 |
Cairns MJ, King A, Sun L-Q, 'Optimisation of the 10±23 DNAzyme±substrate pairing interactions enhanced RNA cleavage activity at purine±cytosine target sites', Nucleic Acids Research, 31 2883-2889 (2003) [C1]
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2003 |
Kim Y, Cairns MJ, Marouga R, Sun L-Q, 'E6AP gene suppression and characterization with in vitro selected hammerhead ribozymes', Cancer Gene Therapy, 10 707-716 (2003) [C1]
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2002 |
Cairns MJ, Saravolac EG, Sun LQ, 'Catalytic DNA: A novel tool for gene suppression', CURRENT DRUG TARGETS, 3 269-279 (2002)
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2000 |
Cairns MJ, King A, Sun LQ, 'Nucleic acid mutation analysis using catalytic DNA.', Nucleic acids research, 28 (2000)
The sequence specificity of the '10-23' RNA-cleaving DNA enzyme (deoxyribozyme) was utilised to discriminate between subtle differences in nucleic acid sequence in a rel... [more]
The sequence specificity of the '10-23' RNA-cleaving DNA enzyme (deoxyribozyme) was utilised to discriminate between subtle differences in nucleic acid sequence in a relatively conserved segment of the L1 gene from a number of different human papilloma virus (HPV) genotypes. DNA enzymes specific for the different HPV types were found to cleave their respective target oligoribonucleotide substrates with high efficiency compared with their unmatched counterparts, which were usually not cleaved or cleaved with very low efficiency. This specificity was achieved despite the existence of only very small differences in the sequence of one binding arm. As an example of how this methodology may be applied to mutation analysis of tissue samples, type-specific deoxyribozyme cleavable substrates were generated by genomic PCR using a chimeric primer containing three bases of RNA. The RNA component enabled each amplicon to be cleavable in the presence of its matching deoxyribozyme. In this format, the specificity of deoxyribozyme cleavage is defined by Watson-Crick interactions between one substrate-binding domain (arm I) and the polymorphic sequence which is amplified during PCR. Deoxy-ribozyme-mediated cleavage of amplicons generated by this method was used to examine the HPV status of genomic DNA derived from Caski cells, which are known to be positive for HPV16. This method is applicable to many types of nucleic acid sequence variation, including single nucleotide polymorphisms.
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2000 |
Sun LQ, Cairns MJ, Saravolac EG, Baker A, Gerlach WL, 'Catalytic nucleic acids: From lab to applications', PHARMACOLOGICAL REVIEWS, 52 325-347 (2000)
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2000 |
Cairns MJ, Hopkins TM, Witherington C, Sun LQ, 'The influence of arm length asymmetry and base substitution on the activity of the 10-23 DNA enzyme', ANTISENSE & NUCLEIC ACID DRUG DEVELOPMENT, 10 323-332 (2000)
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1999 |
Sun LQ, Cairns MJ, Gerlach WL, Witherington C, Wang L, King A, 'Suppression of smooth muscle cell proliferation by a c-myc RNA-cleaving deoxyribozyme', JOURNAL OF BIOLOGICAL CHEMISTRY, 274 17236-17241 (1999)
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1999 |
Temple MD, Cairns MJ, Kim A, Murray V, 'Protein-DNA footprinting of the human epsilon-globin promoter in human intact cells using nitrogen mustard analogues and other DNA-damaging agents', BIOCHIMICA ET BIOPHYSICA ACTA-GENE STRUCTURE AND EXPRESSION, 1445 245-256 (1999)
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1999 |
Cairns MJ, Hopkins TM, Witherington C, Wang L, Sun LQ, 'Target site selection for an RNA-cleaving catalytic DNA', NATURE BIOTECHNOLOGY, 17 480-486 (1999)
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1998 |
Cairns MJ, Murray V, 'The DNA sequence specificity of hedamycin damage determined by ligation-mediated PCR and linear amplification.', BIOCHEMISTRY AND MOLECULAR BIOLOGY INTERNATIONAL, 46 267-275 (1998)
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1998 |
Cairns MJ, Murray V, 'Detection of protein - DNA interactions at beta-globin gene cluster in intact human cells utilizing hedamycin as DNA-damaging agent', DNA AND CELL BIOLOGY, 17 325-333 (1998)
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1997 |
Temple MD, Cairns MJ, Denny WA, Murray V, 'Protein-DNA interactions in the human beta-globin. Locus control region hypersensitive site-2 as revealed by four nitrogen mustards', NUCLEIC ACIDS RESEARCH, 25 3255-3260 (1997)
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1996 |
Cairns MJ, Murray V, 'Influence of chromatin structure on bleomycin-DNA interactions at base pair resolution in the human beta-globin gene cluster', BIOCHEMISTRY, 35 8753-8760 (1996)
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1994 |
CAIRNS MJ, MURRAY V, 'COMPARISON OF THE SEQUENCE SPECIFICITY OF CIS-DIAMINEDICHLOROPLATINUM(II) DAMAGE IN GUANINE-CONTAINING AND 7-DEAZAGUANINE-CONTAINING DNA', BIOCHIMICA ET BIOPHYSICA ACTA-GENE STRUCTURE AND EXPRESSION, 1218 315-321 (1994)
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1994 |
Cairns MJ, Murray V, 'Dideoxy genomic sequencing of a single-copy mammalian gene using more than two hundred cycles of linear amplification', BioTechniques, 17 910-913+914 (1994)
We explored the possibility of using a large number of reaction cycles to achieve genomic DNA sequencing in single-copy mammalian genes. A section of the ß-globin promoter was seq... [more]
We explored the possibility of using a large number of reaction cycles to achieve genomic DNA sequencing in single-copy mammalian genes. A section of the ß-globin promoter was sequenced directly from a sample of human white blood cell DNA. The sequencing fragments were extended from a single, 5'- terminal-labeled oligonucleotide primer by Taq DNA Polymerase in the presence of dideoxyribonucleotides and more than 200 thermal cycles of denaturation, annealing and extension. The labeled sequencing fragments produced in this linear amplification were detected after electrophoresis on a DNA-sequencing gel. We propose that this scheme could be adopted in some instances as an alternative to conventional sequencing.
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1993 |
HALLIDAY GM, CULLEN K, CAIRNS MJ, 'QUANTITATION AND 3-DIMENSIONAL RECONSTRUCTION OF CH4 NUCLEUS IN THE HUMAN BASAL FOREBRAIN', SYNAPSE, 15 1-16 (1993)
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1993 |
MURRAY V, MONCHAWIN C, CAIRNS MJ, ENGLAND PR, LEIGH D, MCDONALD BL, 'DETECTION OF POLYMORPHISMS USING THERMAL CYCLING WITH A SINGLE OLIGONUCLEOTIDE ON A DNA SEQUENCING GEL', HUMAN MUTATION, 2 118-122 (1993)
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