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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Nova |
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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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 |
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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Nova |
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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Nova |
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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Nova |
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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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 |
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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Nova |
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 |
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 |
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 |
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 |
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 |
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 |
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 |
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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