Assoc Prof Paul Tooney

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Background: There is considerable evidence that many complex traits have a partially shared genetic basis, termed pleiotropy. It is therefore useful to consider integrating genome-wide association study (GWAS) data across several traits, usually at the summary statistic level. A major practical challenge arises when these GWAS have overlapping subjects. This is particularly an issue when estimating pleiotropy using methods that condition the significance of one trait on the signficance of a second, such as the covariate-modulated false discovery rate (cmfdr). Results: We propose a method for correcting for sample overlap at the summary statistic level. We quantify the expected amount of spurious correlation between the summary statistics from two GWAS due to sample overlap, and use this estimated correlation in a simple linear correction that adjusts the joint distribution of test statistics from the two GWAS. The correction is appropriate for GWAS with case-control or quantitative outcomes. Our simulations and data example show that without correcting for sample overlap, the cmfdr is not properly controlled, leading to an excessive number of false discoveries and an excessive false discovery proportion. Our correction for sample overlap is effective in that it restores proper control of the false discovery rate, at very little loss in power. Conclusions: With our proposed correction, it is possible to integrate GWAS summary statistics with overlapping samples in a statistical framework that is dependent on the joint distribution of the two GWAS.

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.

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.

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⁺) and somatostatin (SST⁺) 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⁺ IWMN density trended to be higher in offspring from dams exposed to polyI:C at GD19, but not GD10. A subpopulation of these NeuN⁺ IWMNs was shown to express SST. PolyI:C treatment of dams induced a significant increase in the density of SST⁺ 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⁺ and SST⁺ 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.

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.

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.

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.

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.

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).

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.

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.

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.

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.

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).