2024 |
Lozinski M, Bowden NA, Graves MC, Fay M, Day BW, Stringer BW, Tooney PA, 'ATR inhibition using gartisertib enhances cell death and synergises with temozolomide and radiation in patient-derived glioblastoma cell lines.', Oncotarget, 15 1-18 (2024) [C1]
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Nova |
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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Nova |
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 |
Lozinski M, Lumbers ER, Bowden NA, Martin JH, Fay MF, Pringle KG, Tooney PA, 'Upregulation of the Renin-Angiotensin System Is Associated with Patient Survival and the Tumour Microenvironment in Glioblastoma', CELLS, 13 (2024)
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2024 |
Koromina M, Ravi A, Panagiotaropoulou G, Schilder BM, Humphrey J, Braun A, et al., 'Fine-mapping genomic loci refines bipolar disorder risk genes.', medRxiv, (2024)
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2024 |
Boen R, Kaufmann T, van der Meer D, Frei O, Agartz I, Ames D, et al., 'Beyond the Global Brain Differences: Intraindividual Variability Differences in 1q21.1 Distal and 15q11.2 BP1-BP2 Deletion Carriers.', Biol Psychiatry, 95 147-160 (2024) [C1]
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Nova |
2023 |
Maddison K, Bowden NA, Graves MC, Tooney PA, 'Characteristics of vasculogenic mimicry and tumour to endothelial transdifferentiation in human glioblastoma: a systematic review', BMC Cancer, 23 (2023) [C1]
Background: Glioblastoma, the most common primary malignant brain tumour in adults, is a highly vascular tumour characterised by abnormal angiogenesis. Additional mechanisms of tu... [more]
Background: Glioblastoma, the most common primary malignant brain tumour in adults, is a highly vascular tumour characterised by abnormal angiogenesis. Additional mechanisms of tumour vascularisation have also been reported in glioblastoma, including the formation of tumour cell-derived vessels by vasculogenic mimicry (VM) or the transdifferentiation of tumour cells to endothelial cells. VM and endothelial transdifferentiation have frequently been reported as distinct processes, however, the use of both terms to describe a single process of vascularisation also occurs. Some overlapping characteristics have also been reported when identifying each process. We therefore aimed to determine the markers consistently attributed to VM and endothelial transdifferentiation in the glioblastoma literature. Methods: Ovid MEDLINE and Ovid Embase were searched for studies published between January 1999 and July 2021 that assessed VM or tumour to endothelial transdifferentiation in human glioblastoma. The online systematic review tool Covidence was used for screening and data extraction. Extracted data included type of tumour-derived vasculature reported, methods and techniques used, and markers investigated. Studies were grouped based on type of vasculature reported for further assessment. Results: One hundred and thirteen of the 419 unique records identified were included for analysis. VM was reported in 64/113 studies, while tumour to endothelial transdifferentiation was reported in 16/113 studies. The remaining studies used both terms to describe a single process, did not define the process that occurred, or concluded that neither VM nor endothelial transdifferentiation occurred. Absence of CD34 and/or CD31 in vascular structures was the most common indicator of VM, while expression of CD34 and/or CD31, in addition to various other endothelial, stem cell or tumour cell markers, indicated tumour to endothelial transdifferentiation. Conclusion: Cells derived from tumour to endothelial transdifferentiation express typical endothelial markers including CD34 and CD31, while tumour cells contributing to VM lack CD34 and CD31 expression. Additional tumour markers are required to identify transdifferentiation in glioblastoma tissue, and this process requires further characterisation.
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Nova |
2023 |
Brighi C, Puttick S, Woods A, Keall P, Tooney PA, Waddington DEJ, et al., 'Comparison between [68Ga]Ga-PSMA-617 and [18F]FET PET as Imaging Biomarkers in Adult Recurrent Glioblastoma', International Journal of Molecular Sciences, 24 16208-16208 [C1]
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Nova |
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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Nova |
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 |
Maddison K, Faulkner S, Graves MC, Fay M, Bowden NA, Tooney PA, 'Vasculogenic Mimicry Occurs at Low Levels in Primary and Recurrent Glioblastoma', Cancers, 15 3922-3922 [C1]
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Nova |
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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Nova |
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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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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Nova |
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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Nova |
2022 |
Lozinski M, Bowden NA, Graves MC, Fay M, Day BW, Stringer BW, Tooney PA, 'Transcriptomic Profiling of DNA Damage Response in Patient-Derived Glioblastoma Cells before and after Radiation and Temozolomide Treatment', Cells, 11 (2022) [C1]
Glioblastoma is a highly aggressive, invasive and treatment-resistant tumour. The DNA damage response (DDR) provides tumour cells with enhanced ability to activate cell cycle arre... [more]
Glioblastoma is a highly aggressive, invasive and treatment-resistant tumour. The DNA damage response (DDR) provides tumour cells with enhanced ability to activate cell cycle arrest and repair treatment-induced DNA damage. We studied the expression of DDR, its relationship with standard treatment response and patient survival, and its activation after treatment. The transcriptomic profile of DDR pathways was characterised within a cohort of isocitrate dehydrogenase (IDH) wild-type glioblastoma from The Cancer Genome Atlas (TCGA) and 12 patient-derived glioblastoma cell lines. The relationship between DDR expression and patient survival and cell line response to temozolomide (TMZ) or radiation therapy (RT) was assessed. Finally, the expression of 84 DDR genes was examined in glioblastoma cells treated with TMZ and/or RT. Although distinct DDR cluster groups were apparent in the TCGA cohort and cell lines, no significant differences in OS and treatment response were observed. At the gene level, the high expression of ATP23, RAD51C and RPA3 independently associated with poor prognosis in glioblastoma patients. Finally, we observed a substantial upregulation of DDR genes after treatment with TMZ and/or RT, particularly in RTtreated glioblastoma cells, peaking within 24 h after treatment. Our results confirm the potential influence of DDR genes in patient outcome. The observation of DDR genes in response to TMZ and RT gives insight into the global response of DDR pathways after adjuvant treatment in glioblastoma, which may have utility in determining DDR targets for inhibition.
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Nova |
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 |
Lozinski M, Bowden NA, Graves MC, Fay M, Tooney PA, 'DNA damage repair in glioblastoma: current perspectives on its role in tumour progression, treatment resistance and PIKKing potential therapeutic targets', CELLULAR ONCOLOGY, 44 961-981 (2021) [C1]
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Nova |
2021 |
Maddison K, Graves MC, Bowden NA, Fay M, Vilain RE, Faulkner S, Tooney PA, 'Low tumour-infiltrating lymphocyte density in primary and recurrent glioblastoma', Oncotarget, 12 2177-2187 (2021) [C1]
Immunotherapies targeting tumour-infiltrating lymphocytes (TILs) that express the immune checkpoint molecule programmed cell death-1 (PD-1) have shown promise in preclinical gliob... [more]
Immunotherapies targeting tumour-infiltrating lymphocytes (TILs) that express the immune checkpoint molecule programmed cell death-1 (PD-1) have shown promise in preclinical glioblastoma models but have had limited success in clinical trials. To assess when glioblastoma is most likely to benefit from immune checkpoint inhibitors we determined the density of TILs in primary and recurrent glioblastoma. Thirteen cases of matched primary and recurrent glioblastoma tissue were immunohistochemically labelled for CD3, CD8, CD4 and PD-1, and TIL density assessed. CD3+ TILs were observed in all cases, with the majority of both primary (69.2%) and recurrent (61.5%) tumours having low density of TILs present. CD8+ TILs were observed at higher densities than CD4+ TILs in both tumour groups. PD-1+ TILs were sparse and present in only 25% of primary and 50% of recurrent tumours. Quantitative analysis of TILs demonstrated significantly higher CD8+ TIL density at recurrence (p = 0.040). No difference was observed in CD3+ (p = 0.191), CD4+ (p = 0.607) and PD-1+ (p = 0.070) TIL density between primary and recurrent groups. This study shows that TILs are present at low densities in both primary and recurrent glioblastoma. Furthermore, PD-1+ TILs were frequently absent, which may provide evidence as to why anti-PD-1 immunotherapy trials have been largely unsuccessful in glioblastoma.
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Nova |
2021 |
Di Biase MA, Zalesky A, Cetin-Karayumak S, Rathi Y, Lv J, Boerrigter D, et al., 'Large-Scale Evidence for an Association Between Peripheral Inflammation and White Matter Free Water in Schizophrenia and Healthy Individuals', SCHIZOPHRENIA BULLETIN, 47 542-551 (2021) [C1]
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Nova |
2021 |
Mullins N, Forstner AJ, O'Connell KS, Coombes B, Coleman JR, Qiao Z, et al., 'Genome-wide association study of more than 40,000 bipolar disorder cases provides new insights into the underlying biology', NATURE GENETICS, 53 817-+ (2021) [C1]
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Nova |
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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Nova |
2020 |
Richards AL, Pardiñas AF, Frizzati A, Tansey KE, Lynham AJ, Holmans P, et al., 'The Relationship Between Polygenic Risk Scores and Cognition in Schizophrenia', Schizophrenia Bulletin, 46 336-344 (2020) [C1]
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2020 |
Grasby KL, Jahanshad N, Painter JN, Colodro-Conde L, Bralten J, Hibar DP, et al., 'The genetic architecture of the human cerebral cortex', SCIENCE, 367 1340-+ (2020) [C1]
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Nova |
2020 |
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 |
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 |
Duchatel RJ, Harms LR, Meehan CL, Michie PT, Bigland MJ, Smith DW, et al., 'Reduced cortical somatostatin gene expression in a rat model of maternal immune activation', PSYCHIATRY RESEARCH, 282 (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 |
Duchatel RJ, Shannon Weickert C, Tooney PA, 'White matter neuron biology and neuropathology in schizophrenia', npj Schizophrenia, 5 1-9 (2019) [C1]
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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 |
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 |
Hu¨bel C, Gaspar HA, Coleman JRI, Hanscombe KB, Purves K, Prokopenko I, et al., 'Genetic correlations of psychiatric traits with body composition and glycemic traits are sex- and age-dependent', Nature Communications, 10 [C1]
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2019 |
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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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 |
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 |
Duchatel RJ, Meehan CL, Harms LR, Michie PT, Bigland MJ, Smith DW, et al., 'Increased complement component 4 (
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2018 |
Duchatel RJ, Meehan CL, Harms LR, Michie PT, Bigland MJ, Smith DW, et al., 'Late gestation immune activation increases IBA1-positive immunoreactivity levels in the corpus callosum of adult rat offspring', Psychiatry Research, 266 175-185 (2018) [C1]
Animal models of maternal immune activation study the effects of infection, an environmental risk factor for schizophrenia, on brain development. Microglia activation and cytokine... [more]
Animal models of maternal immune activation study the effects of infection, an environmental risk factor for schizophrenia, on brain development. Microglia activation and cytokine upregulation may have key roles in schizophrenia neuropathology. We hypothesised that maternal immune activation induces changes in microglia and cytokines in the brains of the adult offspring. Maternal immune activation was induced by injecting polyriboinosinic:polyribocytidylic acid into pregnant rats on gestational day (GD) 10 or GD19, with brain tissue collected from the offspring at adulthood. We observed no change in Iba1, Gfap, IL1-ß and TNF-a mRNA levels in the cingulate cortex (CC) in adult offspring exposed to maternal immune activation. Prenatal exposure to immune activation had a significant main effect on microglial IBA1-positive immunoreactive material (IBA1+IRM) in the corpus callosum; post-hoc analyses identified a significant increase in GD19 offspring, but not GD10. No change in was observed in the CC. In contrast, maternal immune activation had a significant main effect on GFAP+IRM in the CC at GD19 (not GD10); post-hoc analyses only identified a strong trend towards increased GFAP+IRM in the GD19 offspring, with no white matter changes. This suggests late gestation maternal immune activation causes subtle alterations to microglia and astrocytes in the adult offspring.
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Nova |
2018 |
Li W, Fan CC, Mäki-Marttunen T, Thompson WK, Schork AJ, Bettella F, et al., 'A molecule-based genetic association approach implicates a range of voltage-gated calcium channels associated with schizophrenia', American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 177 454-467 (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 |
Glass LJ, Sinclair D, Boerrigter D, Naude K, Fung SJ, Brown D, et al., 'Brain antibodies in the cortex and blood of people with schizophrenia and controls', TRANSLATIONAL PSYCHIATRY, 7 (2017) [C1]
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Nova |
2017 |
Atkinson RJ, Fulham WR, Michie PT, Ward PB, Todd J, Stain H, et al., 'Electrophysiological, cognitive and clinical profiles of at-risk mental state: The longitudinal Minds in Transition (MinT) study', PLOS ONE, 12 (2017) [C1]
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Nova |
2017 |
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 |
2016 |
Duchatel RJ, Jobling P, Graham BA, Harms LR, Michie PT, Hodgson DM, Tooney PA, 'Increased white matter neuron density in a rat model of maternal immune activation - Implications for schizophrenia', Progress in Neuro-Psychopharmacology and Biological Psychiatry, 65 118-126 (2016) [C1]
Interstitial neurons are located among white matter tracts of the human and rodent brain. Post-mortem studies have identified increased interstitial white matter neuron (IWMN) den... [more]
Interstitial neurons are located among white matter tracts of the human and rodent brain. Post-mortem studies have identified increased interstitial white matter neuron (IWMN) density in the fibre tracts below the cortex in people with schizophrenia. The current study assesses IWMN pathology in a model of maternal immune activation (MIA); a risk factor for schizophrenia. Experimental MIA was produced by an injection of polyinosinic:polycytidylic acid (PolyI:C) into pregnant rats on gestational day (GD) 10 or GD19. A separate control group received saline injections. The density of neuronal nuclear antigen (NeuN<sup>+</sup>) and somatostatin (SST<sup>+</sup>) IWMNs was determined in the white matter of the corpus callosum in two rostrocaudally adjacent areas in the 12week old offspring of GD10 (n=10) or GD19 polyI:C dams (n=18) compared to controls (n=20). NeuN<sup>+</sup> IWMN density trended to be higher in offspring from dams exposed to polyI:C at GD19, but not GD10. A subpopulation of these NeuN<sup>+</sup> IWMNs was shown to express SST. PolyI:C treatment of dams induced a significant increase in the density of SST<sup>+</sup> IWMNs in the offspring when delivered at both gestational stages with more regionally widespread effects observed at GD19. A positive correlation was observed between NeuN<sup>+</sup> and SST<sup>+</sup> IWMN density in animals exposed to polyI:C at GD19, but not controls. This is the first study to show that MIA increases IWMN density in adult offspring in a similar manner to that seen in the brain in schizophrenia. This suggests the MIA model will be useful in future studies aimed at probing the relationship between IWMNs and schizophrenia.
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Nova |
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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Nova |
2016 |
Tooney PA, 'Attention: Schizophrenia Risk Gene Product miR-137 Now Targeting EFNB2', EBIOMEDICINE, 12 10-+ (2016)
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Nova |
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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Nova |
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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Nova |
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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Nova |
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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Nova |
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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Nova |
2016 |
Sekar A, Bialas AR, de Rivera H, Davis A, Hammond TR, Kamitaki N, et al., 'Schizophrenia risk from complex variation of complement component 4', Nature, 530 177-183 (2016) [C1]
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Nova |
2016 |
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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Nova |
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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Nova |
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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Nova |
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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Nova |
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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Nova |
2015 |
Bergon A, Belzeaux R, Comte M, Pelletier F, Hervé M, Gardiner EJ, et al., 'CX3CR1 is dysregulated in blood and brain from schizophrenia patients', Schizophrenia Research, 168 434-443 (2015) [C1]
The molecular mechanisms underlying schizophrenia remain largely unknown. Although schizophrenia is a mental disorder, there is increasing evidence to indicate that inflammatory p... [more]
The molecular mechanisms underlying schizophrenia remain largely unknown. Although schizophrenia is a mental disorder, there is increasing evidence to indicate that inflammatory processes driven by diverse environmental factors play a significant role in its development. With gene expression studies having been conducted across a variety of sample types, e.g., blood and postmortem brain, it is possible to investigate convergent signatures that may reveal interactions between the immune and nervous systems in schizophrenia pathophysiology. We conducted two meta-analyses of schizophrenia microarray gene expression data (N= 474) and non-psychiatric control (N= 485) data from postmortem brain and blood. Then, we assessed whether significantly dysregulated genes in schizophrenia could be shared between blood and brain. To validate our findings, we selected a top gene candidate and analyzed its expression by RT-qPCR in a cohort of schizophrenia subjects stabilized by atypical antipsychotic monotherapy (N= 29) and matched controls (N= 31). Meta-analyses highlighted inflammation as the major biological process associated with schizophrenia and that the chemokine receptor CX3CR1 was significantly down-regulated in schizophrenia. This differential expression was also confirmed in our validation cohort. Given both the recent data demonstrating selective CX3CR1 expression in subsets of neuroimmune cells, as well as behavioral and neuropathological observations of CX3CR1 deficiency in mouse models, our results of reduced CX3CR1 expression adds further support for a role played by monocyte/microglia in the neurodevelopment of schizophrenia.
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Nova |
2015 |
Green MJ, Raudino A, Cairns MJ, Wu J, Tooney PA, Scott RJ, Carr VJ, 'Do common genotypes of FK506 binding protein 5 (FKBP5) moderate the effects of childhood maltreatment on cognition in schizophrenia and healthy controls?', Journal of Psychiatric Research, 70 9-17 (2015) [C1]
Common variants of the FK506 binding protein 5 (FKBP5) gene are implicated in psychotic and other disorders, via their role in regulating glucocorticoid receptor (GR) receptor sen... [more]
Common variants of the FK506 binding protein 5 (FKBP5) gene are implicated in psychotic and other disorders, via their role in regulating glucocorticoid receptor (GR) receptor sensitivity and effects on the broader function of the HPA system in response to stress. In this study, the effects of four FKBP5 polymorphisms (rs1360780, rs9470080, rs4713902, rs9394309) on IQ and eight other cognitive domains were examined in the context of exposure to childhood maltreatment in 444 cases with schizophrenia and 292 healthy controls (from a total sample of 617 cases and 659 controls obtained from the Australian Schizophrenia Research Bank; ASRB). Participants subjected to any kind of maltreatment (including physical, emotional, or sexual abuse or physical or emotional neglect) in childhood were classified as 'exposed'; cognitive functioning was measured with Repeatable Battery for the Assessment of Neuropsychological Status, the Controlled Oral Word Association Test, and IQ was estimated with the Weschler Test of Adult Reading. Hierarchical regressions were used to test the main effects of genotype and childhood maltreatment, and their additive interactive effects, on cognitive function. For rs1360870, there were significant main effects of genotype and childhood maltreatment, and a significant interaction of genotype with childhood trauma affecting attention in both schizophrenia and healthy participants (C-homozygotes in both groups showed worse attention in the context of maltreatment); in SZ, this SNP also affected global neuropsychological function regardless of exposure to childhood trauma, with T-homozygotes showing worse cognition than other genotypes. The mechanisms of trauma-dependent effects of FKBP5 following early life trauma deserve further exploration in healthy and psychotic samples, in the context of epigenetic effects and perhaps epistasis with other genes. Study of these processes may be particularly informative in subgroups exposed to various other forms of early life adversity (i.e., birth complications, immigration).
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Nova |
2015 |
Vilhjálmsson BJ, Yang J, Finucane HK, Gusev A, Lindström S, Ripke S, et al., 'Modeling Linkage Disequilibrium Increases Accuracy of Polygenic Risk Scores', American Journal of Human Genetics, 97 576-592 (2015) [C1]
Polygenic risk scores have shown great promise in predicting complex disease risk and will become more accurate as training sample sizes increase. The standard approach for calcul... [more]
Polygenic risk scores have shown great promise in predicting complex disease risk and will become more accurate as training sample sizes increase. The standard approach for calculating risk scores involves linkage disequilibrium (LD)-based marker pruning and applying a p value threshold to association statistics, but this discards information and can reduce predictive accuracy. We introduce LDpred, a method that infers the posterior mean effect size of each marker by using a prior on effect sizes and LD information from an external reference panel. Theory and simulations show that LDpred outperforms the approach of pruning followed by thresholding, particularly at large sample sizes. Accordingly, predicted R2 increased from 20.1% to 25.3% in a large schizophrenia dataset and from 9.8% to 12.0% in a large multiple sclerosis dataset. A similar relative improvement in accuracy was observed for three additional large disease datasets and for non-European schizophrenia samples. The advantage of LDpred over existing methods will grow as sample sizes increase.
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Nova |
2015 |
Finucane HK, Bulik-Sullivan B, Gusev A, Trynka G, Reshef Y, Loh P-R, et al., 'Partitioning heritability by functional annotation using genome-wide association summary statistics', Nature Genetics, 47 1228-1235 (2015) [C1]
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Nova |
2015 |
Loh P-R, Bhatia G, Gusev A, Finucane HK, Bulik-Sullivan BK, Pollack SJ, et al., 'Contrasting genetic architectures of schizophrenia and other complex diseases using fast variance-components analysis', Nature Genetics, 47 1385-1392 (2015) [C1]
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Nova |
2015 |
Ingason A, Giegling I, Hartmann AM, Genius J, Konte B, Friedl M, et al., 'Expression analysis in a rat psychosis model identifies novel candidate genes validated in a large case control sample of schizophrenia', Translational Psychiatry, 5 e656-e656 [C1]
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Nova |
2015 |
Cropley VL, Scarr E, Fornito A, Klauser P, Bousman CA, Scott R, et al., 'The effect of a muscarinic receptor 1 gene variant on grey matter volume in schizophrenia', Psychiatry Research - Neuroimaging, 234 182-187 (2015) [C1]
Previous research has demonstrated that individuals with schizophrenia who are homozygous at the c.267C>A single nucleotide polymorphism (rs2067477) within the cholinergic musc... [more]
Previous research has demonstrated that individuals with schizophrenia who are homozygous at the c.267C>A single nucleotide polymorphism (rs2067477) within the cholinergic muscarinic M1 receptor (CHRM1) perform less well on the Wisconsin Card Sorting Test (WCST) than those who are heterozygous. This study sought to determine whether variation in the rs2067477 genotype was associated with differential changes in brain structure. Data from 227 patients with established schizophrenia or schizoaffective disorder were obtained from the Australian Schizophrenia Research Bank. Whole-brain voxel-based morphometry was performed to compare regional grey matter volume (GMV) between the 267C/C (N=191) and 267C/A (N=36) groups. Secondary analyses tested for an effect of genotype on cognition (the WCST was not available). Individuals who were homozygous (267C/C) demonstrated significantly reduced GMV in the right precentral gyrus compared to those who were heterozygous (267C/A). These preliminary results suggest that the rs2067477 genotype is associated with brain structure in the right precentral gyrus in individuals with schizophrenia/schizoaffective disorder. Future studies are required to replicate these results and directly link the volumetric reductions with specific cognitive processes.
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Nova |
2014 |
Oldmeadow C, Mossman D, Evans T-J, Holliday EG, Tooney PA, Cairns MJ, et al., 'Combined analysis of exon splicing and genome wide polymorphism data predict schizophrenia risk loci.', J Psychiatr Res, 52 44-49 (2014) [C1]
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Nova |
2014 |
Gusev A, Lee SH, Trynka G, Finucane H, Vilhjálmsson BJ, Xu H, et al., 'Partitioning Heritability of Regulatory and Cell-Type-Specific Variants across 11 Common Diseases', The American Journal of Human Genetics, 95 535-552 (2014) [C1]
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Nova |
2014 |
McCarthy-Jones S, Green MJ, Scott RJ, Tooney PA, Cairns MJ, Wu JQ, et al., 'Preliminary evidence of an interaction between the
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Nova |
2014 |
Green MJ, Chia TY, Cairns MJ, Wu J, Tooney PA, Scott RJ, Carr VJ, 'Catechol-O-methyltransferase (COMT) genotype moderates the effects of childhood trauma on cognition and symptoms in schizophrenia', Journal of Psychiatric Research, 49 43-50 (2014) [C1]
The interaction of genetic and environmental factors may affect the course and development of psychotic disorders. We examined whether the effects of childhood trauma on cognition... [more]
The interaction of genetic and environmental factors may affect the course and development of psychotic disorders. We examined whether the effects of childhood trauma on cognition and symptoms in schizophrenia were moderated by the Catechol-O-methyltransferase (COMT) Val158Met polymorphism, a common genetic variant known to affect cognition and prefrontal dopamine levels. Participants were 429 schizophrenia/schizoaffective cases from the Australian Schizophrenia Research Bank (ASRB). Cognitive performance was assessed using the Repeatable Battery for Assessment of Neuropsychological Status (RBANS), Controlled Oral Word Association Test (COWAT), Letter Number Sequencing (LNS) test, and the Wechsler Test of Adult Reading (WTAR). Hierarchical regression was used to test the main effects and additive interaction effects of genotype and childhood trauma in the domains of physical abuse, emotional abuse, and emotional neglect, on cognition and symptom profiles of clinical cases. Consistent with previous findings, COMT Val homozygotes performed worse on cognitive measures in the absence of childhood adversity. In addition, a significant interaction between COMT genotype and physical abuse was associated with better executive function in Val homozygotes, relative to those of the same genotype with no history of abuse. Finally, the severity of positive symptoms was greater in Met carriers who had experienced physical abuse, and the severity of negative symptoms in Met carriers was greater in the presence of emotional neglect. These results suggest that the possible epigenetic modulation of the expression of the COMT Val158Met polymorphism and consequent effects on cognition and symptoms in schizophrenia, with worse outcomes associated with adverse childhood experiences in Met carriers. © 2013 Elsevier Ltd.
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Nova |
2014 |
Kumarasinghe N, Rasser PE, Mendis J, Bergmann J, Knechtel L, Oxley S, et al., 'Age effects on cerebral grey matter and their associations with psychopathology, cognition and treatment response in previously untreated schizophrenia patients', Neurology Psychiatry and Brain Research, 20 29-36 (2014) [C1]
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Nova |
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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Nova |
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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Nova |
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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Nova |
2013 |
Green MJ, Cairns MJ, Wu J, Dragovic M, Jablensky A, Tooney PA, et al., 'Genome-wide supported variant
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Nova |
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 |
Kumarasinghe N, Beveridge NJ, Gardiner E, Scott RJ, Yasawardene S, Perera A, et al., 'Gene expression profiling in treatment-naive schizophrenia patients identifies abnormalities in biological pathways involving
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Nova |
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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Nova |
2012 |
Kumarasinghe KMN, Tooney PA, Schall UA, 'Finding the needle in the haystack: A review of microarray gene expression research into schizophrenia', Australian and New Zealand Journal of Psychiatry, 46 598-610 (2012) [C1]
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Nova |
2012 |
Gardiner EJ, Beveridge NJ, Wu JQ, Carr VJ, Scott R, Tooney PA, Cairns MJ, 'Imprinted DLK1-DIO3 region of 14q32 defines a schizophrenia-associated miRNA signature in peripheral blood mononuclear cells', Molecular Psychiatry, 17 827-840 (2012) [C1]
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Nova |
2012 |
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 |
Wu JQ, Wang X, Beveridge NJ, Tooney PA, Scott R, Carr VJ, Cairns MJ, 'Transcriptome sequencing revealed significant alteration of cortical promoter usage and splicing in schizophrenia', PLoS One, 7 (2012) [C1]
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Nova |
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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Nova |
2011 |
Case VS, Soyland A, Tooney PA, Thompson PM, Rasser PE, Schall UA, et al., 'Gray matter deficits, mismatch negativity, and outcomes in schizophrenia', Schizophrenia Bulletin, 37 131-140 (2011) [C1]
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Nova |
2010 |
Loughland CM, Draganic D, McCabe KL, Richards JM, Nasir MA, Allen J, et al., 'Australian Schizophrenia Research Bank: A database of comprehensive clinical, endophenotypic and genetic data for aetiological studies of schizophrenia', Australian and New Zealand Journal of Psychiatry, 44 1029-1035 (2010) [C1]
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Nova |
2010 |
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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Nova |
2009 |
Anderson WB, Graham BA, Beveridge NJ, Tooney PA, Brichta AM, Callister RJ, 'Different forms of glycine- and GABA(A)-receptor mediated inhibitory synaptic transmission in mouse superficial and deep dorsal horn neurons', Molecular Pain, 5 1-16 (2009) [C1]
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Nova |
2009 |
Weidenhofer JC, Scott R, Tooney PA, 'Investigation of the expression of genes affecting cytomatrix active zone function in the amygdala in schizophrenia: Effects of antipsychotic drugs', Journal of Psychiatric Research, 43 282-290 (2009) [C1]
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Nova |
2009 |
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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Nova |
2008 |
Bowden NA, Scott R, Tooney PA, 'Altered gene expression in the superior temporal gyrus in schizophrenia', BMC Genomics, 9 1-12 (2008) [C1]
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Nova |
2008 |
Beveridge NJ, Tooney PA, Carroll AP, Gardiner EJ, Bowden NA, Scott R, et al., 'Dysregulation of miRNA 181b in the temporal cortex in schizophrenia', Human Molecular Genetics, 17 1156-1168 (2008) [C1]
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Nova |
2007 |
Bowden NA, Scott R, Tooney PA, 'Altered expression of regulator of G-protein signalling 4 (RGS4) mRNA in the superior temporal gyrus in schizophrenia', Schizophrenia Research, 89 165-168 (2007) [C1]
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2006 |
Weidenhofer JC, Bowden NA, Scott R, Tooney PA, 'Altered gene expression in the amygdala in schizophrenia: Up-regulation of genes located in the cytomatrix active zone', Molecular and Cellular Neuroscience, 31 243-250 (2006) [C1]
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2006 |
Weidenhofer JC, Yip JR, Zavitsanou K, Huang XF, Chahl LA, Tooney PA, 'Immunohistochemical localisation of the NK1 receptor in the human amygdala: Preliminary investigation in schizophrenia', Progress in Neuro-Psychopharmacology and Biological Psychiatry, 30 1313-1321 (2006) [C1]
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2006 |
Bowden NA, Weidenhofer JC, Scott R, Schall U, Todd J, Michie PT, Tooney PA, 'Preliminary investigation of gene expression profiles in peripheral blood lymphocytes in schizophrenia', Schizophrenia Research, 82 175-183 (2006) [C1]
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Nova |
2006 |
Bowden NA, Tooney PA, Scott R, 'Gene expression profiling of xeroderma pigmentosum', Hereditary Cancer in Clinical Practice, 4 103-110 (2006) [C1]
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Nova |
2006 |
Weidenhofer J, Bowden NA, Scott RJ, Tooney PA, 'Dysfunction of genes regulating membrane exocytosis in schizophrenia', AUSTRALIAN AND NEW ZEALAND JOURNAL OF PSYCHIATRY, 40 A129-A129 (2006)
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2005 |
Tooney PA, Anderson WB, Lynch-Frame AM, Chahl LA, 'The effects of haloperidol treatment on the distribution of NK1 receptor immunoreactive neurons in guinea-pig brain (Short Communication)', Neuroscience Letters, 383 155-159 (2005) [C1]
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2004 |
Tooney PA, Chahl LA, 'Neurons expressing calcium-binding proteins in the prefrontal cortex in schizophrenia', Progress in Neuro-Psychopharmacology & Biological Psychiatry, 28 273-278 (2004) [C1]
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2002 |
Tooney PA, Yip J, Zavitsanou K, Huang X-F, Chahl LA, 'Distribution of Tachykinin Receptors in the Human Amygdala', Proceedings of the Australian Neuroscience Society, 13 182 (2002) [C3] |
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2001 |
Tooney PA, Crawter VC, Chahl LA, 'Increased Tachykinin NK1 Receptor Immunoreactivity in the Prefrontal Cortex in Schizophrenia', Biological Psychiatry, 49 523-527 (2001) [C1]
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Nova |
2001 |
Tooney PA, Crawter VC, Chahl LA, 'Tachykinin NK1 receptor immunoreactivity is increased in the prefrontal cortex in schizophrenia', SCHIZOPHRENIA RESEARCH, 49 64-64 (2001) |
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2000 |
Tooney PA, Au GG, Chahl LA, 'Localisation of tachykinin NK1 and NK3 receptors in the human prefrontal and visual cortex', Neuroscience Letters, 283 185-188 (2000) [C1]
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Nova |
1998 |
Tooney PA, Sakai T, Sakai K, Aeschlimann D, Mosher DF, 'Restricted localization of thrombospondin-2 protein during mouse embryogenesis: A comparison to thrombospondin-1', MATRIX BIOLOGY, 17 (2) 131-143 (1998) [C1]
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1993 |
AGREZ MV, TOONEY P, BURNS GF, 'SRC-RELATED PROTEIN TYROSINE KINASES ARE INVOLVED IN INTEGRIN-MEDIATED COLLAGEN REORGANIZATION BY FIBROBLASTS', JOURNAL OF CELLULAR BIOCHEMISTRY, 113-113 (1993) |
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1993 |
BURNS GF, TOONEY PA, MELDRUM CJ, 'GLYCOPROTEIN-88 (CD36) BINDS TUBULIN AND ENDOGENOUS THROMBOSPONDIN', JOURNAL OF CELLULAR BIOCHEMISTRY, 158-158 (1993) |
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1993 |
BURNS GF, TOONEY P, DENICHILO M, MELDRUM C, DORAHY D, 'THE BIOLOGY OF CD36 - AN INTEGRIN-ASSOCIATED ADHESION MOLECULE', JOURNAL OF LEUKOCYTE BIOLOGY, 109-109 (1993) |
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1993 |
Tooney P, Agrez MV, Burns GF, 'A re-examination of the molecular mechanism of cell movement', Immunology and Cell Biology, 71 131-139 (1993) [C1]
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1990 |
Smart YC, Tooney PA, Farrelly ML, Brien JH, Burton RC, 'Natural cytotoxic cells and tumour surveillance', European Journal of Cancer, 26 863-864 (1990) [C1]
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