Connectome architecture shapes large-scale cortical alterations in schizophrenia: a worldwide ENIGMA study.

Schizophrenia is a prototypical network disorder with widespread brain-morphological alterations, yet it remains unclear whether these distributed alterations robustly reflect the underlying network layout. We tested whether large-scale structural alterations in schizophrenia relate to normative structural and functional connectome architecture, and systematically evaluated robustness and generalizability of these network-level alterations. Leveraging anatomical MRI scans from 2439 adults with schizophrenia and 2867 healthy controls from 26 ENIGMA sites and normative data from the Human Connectome Project (n = 207), we evaluated structural alterations of schizophrenia against two network susceptibility models: (i) hub vulnerability, which examines associations between regional network centrality and magnitude of disease-related alterations; (ii) epicenter mapping, which identifies regions whose typical connectivity profile most closely resembles the disease-related morphological alterations. To assess generalizability and specificity, we contextualized the influence of site, disease stages, and individual clinical factors and compared network associations of schizophrenia with that found in affective disorders. Our findings show schizophrenia-related cortical thinning is spatially associated with functional and structural hubs, suggesting that highly interconnected regions are more vulnerable to morphological alterations. Predominantly temporo-paralimbic and frontal regions emerged as epicenters with connectivity profiles linked to schizophrenia's alteration patterns. Findings were robust across sites, disease stages, and related to individual symptoms. Moreover, transdiagnostic comparisons revealed overlapping epicenters in schizophrenia and bipolar, but not major depressive disorder, suggestive of a pathophysiological continuity within the schizophrenia-bipolar-spectrum. In sum, cortical alterations over the course of schizophrenia robustly follow brain network architecture, emphasizing marked hub susceptibility and temporo-frontal epicenters at both the level of the group and the individual. Subtle variations of epicenters across disease stages suggest interacting pathological processes, while associations with patient-specific symptoms support additional inter-individual variability of hub vulnerability and epicenters in schizophrenia. Our work outlines potential pathways to better understand macroscale structural alterations, and inter- individual variability in schizophrenia.

PI3K/mTOR is a therapeutically targetable genetic dependency in diffuse intrinsic pontine glioma.

Diffuse midline glioma (DMG), including tumors diagnosed in the brainstem (diffuse intrinsic pontine glioma; DIPG), are uniformly fatal brain tumors that lack effective treatment. Analysis of CRISPR/Cas9 loss-of-function gene deletion screens identified PIK3CA and MTOR as targetable molecular dependencies across patient derived models of DIPG, highlighting the therapeutic potential of the blood-brain barrier-penetrant PI3K/Akt/mTOR inhibitor, paxalisib. At the human-equivalent maximum tolerated dose, mice treated with paxalisib experienced systemic glucose feedback and increased insulin levels commensurate with patients using PI3K inhibitors. To exploit genetic dependence and overcome resistance while maintaining compliance and therapeutic benefit, we combined paxalisib with the antihyperglycemic drug metformin. Metformin restored glucose homeostasis and decreased phosphorylation of the insulin receptor in vivo, a common mechanism of PI3K-inhibitor resistance, extending survival of orthotopic models. DIPG models treated with paxalisib increased calcium-activated PKC signaling. The brain penetrant PKC inhibitor enzastaurin, in combination with paxalisib, synergistically extended the survival of multiple orthotopic patient-derived and immunocompetent syngeneic allograft models; benefits potentiated in combination with metformin and standard-of-care radiotherapy. Therapeutic adaptation was assessed using spatial transcriptomics and ATAC-Seq, identifying changes in myelination and tumor immune microenvironment crosstalk. Collectively, this study has identified what we believe to be a clinically relevant DIPG therapeutic combinational strategy.

Genetic influences on circulating retinol and its relationship to human health.

Retinol is a fat-soluble vitamin that plays an essential role in many biological processes throughout the human lifespan. Here, we perform the largest genome-wide association study (GWAS) of retinol to date in up to 22,274 participants. We identify eight common variant loci associated with retinol, as well as a rare-variant signal. An integrative gene prioritisation pipeline supports novel retinol-associated genes outside of the main retinol transport complex (RBP4:TTR) related to lipid biology, energy homoeostasis, and endocrine signalling. Genetic proxies of circulating retinol were then used to estimate causal relationships with almost 20,000 clinical phenotypes via a phenome-wide Mendelian randomisation study (MR-pheWAS). The MR-pheWAS suggests that retinol may exert causal effects on inflammation, adiposity, ocular measures, the microbiome, and MRI-derived brain phenotypes, amongst several others. Conversely, circulating retinol may be causally influenced by factors including lipids and serum creatinine. Finally, we demonstrate how a retinol polygenic score could identify individuals more likely to fall outside of the normative range of circulating retinol for a given age. In summary, this study provides a comprehensive evaluation of the genetics of circulating retinol, as well as revealing traits which should be prioritised for further investigation with respect to retinol related therapies or nutritional intervention.

A primer on the use of machine learning to distil knowledge from data in biological psychiatry.

Applications of machine learning in the biomedical sciences are growing rapidly. This growth has been spurred by diverse cross-institutional and interdisciplinary collaborations, public availability of large datasets, an increase in the accessibility of analytic routines, and the availability of powerful computing resources. With this increased access and exposure to machine learning comes a responsibility for education and a deeper understanding of its bases and bounds, borne equally by data scientists seeking to ply their analytic wares in medical research and by biomedical scientists seeking to harness such methods to glean knowledge from data. This article provides an accessible and critical review of machine learning for a biomedically informed audience, as well as its applications in psychiatry. The review covers definitions and expositions of commonly used machine learning methods, and historical trends of their use in psychiatry. We also provide a set of standards, namely Guidelines for REporting Machine Learning Investigations in Neuropsychiatry (GREMLIN), for designing and reporting studies that use machine learning as a primary data-analysis approach. Lastly, we propose the establishment of the Machine Learning in Psychiatry (MLPsych) Consortium, enumerate its objectives, and identify areas of opportunity for future applications of machine learning in biological psychiatry. This review serves as a cautiously optimistic primer on machine learning for those on the precipice as they prepare to dive into the field, either as methodological practitioners or well-informed consumers.

Linking Polygenic Risk of Schizophrenia to Variation in Magnetic Resonance Imaging Brain Measures: A Comprehensive Systematic Review.

BACKGROUND AND HYPOTHESIS: Schizophrenia is highly heritable, with a polygenic effect of many genes conferring risk. Evidence on whether cumulative risk also predicts alterations in brain morphology and function is inconsistent. This systematic review examined evidence for schizophrenia polygenic risk score (sczPRS) associations with commonly used magnetic resonance imaging (MRI) measures. We expected consistent evidence to emerge for significant sczPRS associations with variation in structure and function, specifically in frontal, temporal, and insula cortices that are commonly implicated in schizophrenia pathophysiology. STUDY DESIGN: In accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we searched MEDLINE, Embase, and PsycINFO for peer-reviewed studies published between January 2013 and March 2022. Studies were screened against predetermined criteria and National Institutes of Health (NIH) quality assessment tools. STUDY RESULTS: In total, 57 studies of T1-weighted structural, diffusion, and functional MRI were included (age range = 9-80 years, Nrange = 64-76 644). We observed moderate, albeit preliminary, evidence for higher sczPRS predicting global reductions in cortical thickness and widespread variation in functional connectivity, and to a lesser extent, region-specific reductions in frontal and temporal volume and thickness. Conversely, sczPRS does not predict whole-brain surface area or gray/white matter volume. Limited evidence emerged for sczPRS associations with diffusion tensor measures of white matter microstructure in a large community sample and smaller cohorts of children and young adults. These findings were broadly consistent across community and clinical populations. CONCLUSIONS: Our review supports the hypothesis that schizophrenia is a disorder of disrupted within and between-region brain connectivity, and points to specific whole-brain and regional MRI metrics that may provide useful intermediate phenotypes.

Alteration of DNA Methylation and Epigenetic Scores Associated With Features of Schizophrenia and Common Variant Genetic Risk.

BACKGROUND: Unpacking molecular perturbations associated with features of schizophrenia is a critical step toward understanding phenotypic heterogeneity in this disorder. Recent epigenome-wide association studies have uncovered pervasive dysregulation of DNA methylation in schizophrenia; however, clinical features of the disorder that account for a large proportion of phenotypic variability are relatively underexplored. METHODS: We comprehensively analyzed patterns of DNA methylation in a cohort of 381 individuals with schizophrenia from the deeply phenotyped Australian Schizophrenia Research Bank. Epigenetic changes were investigated in association with cognitive status, age of onset, treatment resistance, Global Assessment of Functioning scores, and common variant polygenic risk scores for schizophrenia. We subsequently explored alterations within genes previously associated with psychiatric illness, phenome-wide epigenetic covariance, and epigenetic scores. RESULTS: Epigenome-wide association studies of the 5 primary traits identified 662 suggestively significant (p < 6.72 × 10-5) differentially methylated probes, with a further 432 revealed after controlling for schizophrenia polygenic risk on the remaining 4 traits. Interestingly, we uncovered many probes within genes associated with a variety of psychiatric conditions as well as significant epigenetic covariance with phenotypes and exposures including acute myocardial infarction, C-reactive protein, and lung cancer. Epigenetic scores for treatment-resistant schizophrenia strikingly exhibited association with clozapine administration, while epigenetic proxies of plasma protein expression, such as CCL17, MMP10, and PRG2, were associated with several features of schizophrenia. CONCLUSIONS: Our findings collectively provide novel evidence suggesting that several features of schizophrenia are associated with alteration of DNA methylation, which may contribute to interindividual phenotypic variation in affected individuals.

Using Genetics to Inform Interventions Related to Sodium and Potassium in Hypertension.

BACKGROUND: Hypertension is a key risk factor for major adverse cardiovascular events but remains difficult to treat in many individuals. Dietary interventions are an effective approach to lower blood pressure (BP) but are not equally effective across all individuals. BP is heritable, and genetics may be a useful tool to overcome treatment response heterogeneity. We investigated whether the genetics of BP could be used to identify individuals with hypertension who may receive a particular benefit from lowering sodium intake and boosting potassium levels. METHODS: In this observational genetic study, we leveraged cross-sectional data from up to 296 475 genotyped individuals drawn from the UK Biobank cohort for whom BP and urinary electrolytes (sodium and potassium), biomarkers of sodium and potassium intake, were measured. Biologically directed genetic scores for BP were constructed specifically among pathways related to sodium and potassium biology (pharmagenic enrichment scores), as well as unannotated genome-wide scores (conventional polygenic scores). We then tested whether there was a gene-by-environment interaction between urinary electrolytes and these genetic scores on BP. RESULTS: Genetic risk and urinary electrolytes both independently correlated with BP. However, urinary sodium was associated with a larger BP increase among individuals with higher genetic risk in sodium- and potassium-related pathways than in those with comparatively lower genetic risk. For example, each SD in urinary sodium was associated with a 1.47-mm Hg increase in systolic BP for those in the top 10% of the distribution of genetic risk in sodium and potassium transport pathways versus a 0.97-mm Hg systolic BP increase in the lowest 10% (P=1.95×10-3). This interaction with urinary sodium remained when considering estimated glomerular filtration rate and indexing sodium to urinary creatinine. There was no strong evidence of an interaction between urinary sodium and a standard genome-wide polygenic score of BP. CONCLUSIONS: The data suggest that genetic risk in sodium and potassium pathways could be used in a precision medicine model to direct interventions more specifically in the management of hypertension. Intervention studies are warranted.

Beyond the Global Brain Differences: Intraindividual Variability Differences in 1q21.1 Distal and 15q11.2 BP1-BP2 Deletion Carriers.

BACKGROUND: Carriers of the 1q21.1 distal and 15q11.2 BP1-BP2 copy number variants exhibit regional and global brain differences compared with noncarriers. However, interpreting regional differences is challenging if a global difference drives the regional brain differences. Intraindividual variability measures can be used to test for regional differences beyond global differences in brain structure. METHODS: Magnetic resonance imaging data were used to obtain regional brain values for 1q21.1 distal deletion (n = 30) and duplication (n = 27) and 15q11.2 BP1-BP2 deletion (n = 170) and duplication (n = 243) carriers and matched noncarriers (n = 2350). Regional intra-deviation scores, i.e., the standardized difference between an individual's regional difference and global difference, were used to test for regional differences that diverge from the global difference. RESULTS: For the 1q21.1 distal deletion carriers, cortical surface area for regions in the medial visual cortex, posterior cingulate, and temporal pole differed less and regions in the prefrontal and superior temporal cortex differed more than the global difference in cortical surface area. For the 15q11.2 BP1-BP2 deletion carriers, cortical thickness in regions in the medial visual cortex, auditory cortex, and temporal pole differed less and the prefrontal and somatosensory cortex differed more than the global difference in cortical thickness. CONCLUSIONS: We find evidence for regional effects beyond differences in global brain measures in 1q21.1 distal and 15q11.2 BP1-BP2 copy number variants. The results provide new insight into brain profiling of the 1q21.1 distal and 15q11.2 BP1-BP2 copy number variants, with the potential to increase understanding of the mechanisms involved in altered neurodevelopment.

Estimating multimodal brain variability in schizophrenia spectrum disorders: A worldwide ENIGMA study.

Objective: Schizophrenia is a multifaceted disorder associated with structural brain heterogeneity. Despite its relevance for identifying illness subtypes and informative biomarkers, structural brain heterogeneity in schizophrenia remains incompletely understood. Therefore, the objective of this study was to provide a comprehensive insight into the structural brain heterogeneity associated with schizophrenia. Methods: This meta- and mega-analysis investigated the variability of multimodal structural brain measures of white and gray matter in individuals with schizophrenia versus healthy controls. Using the ENIGMA dataset of MRI-based brain measures from 22 international sites with up to 6139 individuals for a given brain measure, we examined variability in cortical thickness, surface area, folding index, subcortical volume and fractional anisotropy. Results: We found that individuals with schizophrenia are distinguished by higher heterogeneity in the frontotemporal network with regard to multimodal structural measures. Moreover, individuals with schizophrenia showed higher homogeneity of the folding index, especially in the left parahippocampal region. Conclusions: Higher multimodal heterogeneity in frontotemporal regions potentially implies different subtypes of schizophrenia that converge on impaired frontotemporal interaction as a core feature of the disorder. Conversely, more homogeneous folding patterns in the left parahippocampal region might signify a consistent characteristic of schizophrenia shared across subtypes. These findings underscore the importance of structural brain variability in advancing our neurobiological understanding of schizophrenia, and aid in identifying illness subtypes as well as informative biomarkers.

miRNA cargo in circulating vesicles from neurons is altered in individuals with schizophrenia and associated with severe disease.

While RNA expression appears to be altered in several brain disorders, the constraints of postmortem analysis make it impractical for well-powered population studies and biomarker development. Given that the unique molecular composition of neurons are reflected in their extracellular vesicles (EVs), we hypothesized that the fractionation of neuron derived EVs provides an opportunity to specifically profile their encapsulated contents noninvasively from blood. To investigate this hypothesis, we determined miRNA expression in microtubule associated protein 1B (MAP1B)-enriched serum EVs derived from neurons from a large cohort of individuals with schizophrenia and nonpsychiatric comparison participants. We observed dysregulation of miRNA in schizophrenia subjects, in particular those with treatment-resistance and severe cognitive deficits. These data support the hypothesis that schizophrenia is associated with alterations in posttranscriptional regulation of synaptic gene expression and provides an example of the potential utility of tissue-specific EV analysis in brain disorders.

Exploring opportunities for drug repurposing and precision medicine in cannabis use disorder using genetics.

Cannabis use disorder (CUD) remains a significant public health issue globally, affecting up to one in five adults who use cannabis. Despite extensive research into the molecular underpinnings of the condition, there are no effective pharmacological treatment options available. Therefore, we sought to further explore genetic analyses to prioritise opportunities to repurpose existing drugs for CUD. Specifically, we aimed to identify druggable genes associated with the disorder, integrate transcriptomic/proteomic data and estimate genetic relationships with clinically actionable biochemical traits. Aggregating variants to genes based on genomic position, prioritised the phosphodiesterase gene PDE4B as an interesting target for drug repurposing in CUD. Credible causal PDE4B variants revealed by probabilistic finemapping in and around this locus demonstrated an association with inflammatory and other substance use phenotypes. Gene and protein expression data integrated with the GWAS data revealed a novel CUD associated gene, NPTX1, in whole blood and supported a role for hyaluronidase, a key enzyme in the extracellular matrix in the brain and other tissues. Finally, genetic correlation with biochemical traits revealed a genetic overlap between CUD and immune-related markers such as lymphocyte count, as well as serum triglycerides.

Extension of mRNA poly(A) tails and 3'UTRs during neuronal differentiation exhibits variable association with post-transcriptional dynamics.

Differentiation of neural progenitor cells into mature neuronal phenotypes relies on extensive temporospatial coordination of mRNA expression to support the development of functional brain circuitry. Cleavage and polyadenylation of mRNA has tremendous regulatory capacity through the alteration of mRNA stability and modulation of microRNA (miRNA) function, however the extent of utilization in neuronal development is currently unclear. Here, we employed poly(A) tail sequencing, mRNA sequencing, ribosome profiling and small RNA sequencing to explore the functional relationship between mRNA abundance, translation, poly(A) tail length, alternative polyadenylation (APA) and miRNA expression in an in vitro model of neuronal differentiation. Differential analysis revealed a strong bias towards poly(A) tail and 3'UTR lengthening during differentiation, both of which were positively correlated with changes in mRNA abundance, but not translation. Globally, changes in miRNA expression were predominantly associated with mRNA abundance and translation, however several miRNA-mRNA pairings with potential to regulate poly(A) tail length were identified. Furthermore, 3'UTR lengthening was observed to significantly increase the inclusion of non-conserved miRNA binding sites, potentially enhancing the regulatory capacity of these molecules in mature neuronal cells. Together, our findings suggest poly(A) tail length and APA function as part of a rich post-transcriptional regulatory matrix during neuronal differentiation.

Multiomic prioritisation of risk genes for anorexia nervosa.

BACKGROUND: Anorexia nervosa (AN) is a psychiatric disorder associated with marked morbidity. Whilst AN genetic studies could identify novel treatment targets, integration of functional genomics data, including transcriptomics and proteomics, would assist to disentangle correlated signals and reveal causally associated genes. METHODS: We used models of genetically imputed expression and splicing from 14 tissues, leveraging mRNA, protein, and mRNA alternative splicing weights to identify genes, proteins, and transcripts, respectively, associated with AN risk. This was accomplished through transcriptome, proteome, and spliceosome-wide association studies, followed by conditional analysis and finemapping to prioritise candidate causal genes. RESULTS: We uncovered 134 genes for which genetically predicted mRNA expression was associated with AN after multiple-testing correction, as well as four proteins and 16 alternatively spliced transcripts. Conditional analysis of these significantly associated genes on other proximal association signals resulted in 97 genes independently associated with AN. Moreover, probabilistic finemapping further refined these associations and prioritised putative causal genes. The gene WDR6, for which increased genetically predicted mRNA expression was correlated with AN, was strongly supported by both conditional analyses and finemapping. Pathway analysis of genes revealed by finemapping identified the pathway regulation of immune system process (overlapping genes = MST1, TREX1, PRKAR2A, PROS1) as statistically overrepresented. CONCLUSIONS: We leveraged multiomic datasets to genetically prioritise novel risk genes for AN. Multiple-lines of evidence support that WDR6 is associated with AN, whilst other prioritised genes were enriched within immune related pathways, further supporting the role of the immune system in AN.

CircRNA and Ageing.

Circular RNAs (circRNAs) are closed-loop RNA transcripts formed by a noncanonical back splicing mechanism. circRNAs are expressed in various tissues and cell types in a temporospatially regulated manner and have diverse molecular functions including their ability to act as miRNA sponges, transcriptional and splicing regulators, protein traps, and even templates for polypeptide synthesis. Emerging evidence suggests that circRNAs are themselves dynamically regulated throughout development in various organisms, with a substantial accumulation during ageing. Their regulatory roles in cellular pathways associated with ageing and senescence, as well as their implications in ageing-related diseases, such as neurological disease, cancer, and cardiovascular disease, suggest that circRNAs are key molecular determinants of the ageing process. Their unique structure, expression specificity, and biological functions highlight a potential capacity for use as novel biomarkers for diagnosis, prognosis, and treatment outcomes in a variety of conditions including pathological ageing. CircRNA may also have potential as target for interventions that manipulate ageing and longevity. In this chapter, we discuss the most recent advances in circRNA changes in ageing and ageing-associated disease.

Data analysis guidelines for single-cell RNA-seq in biomedical studies and clinical applications.

The application of single-cell RNA sequencing (scRNA-seq) in biomedical research has advanced our understanding of the pathogenesis of disease and provided valuable insights into new diagnostic and therapeutic strategies. With the expansion of capacity for high-throughput scRNA-seq, including clinical samples, the analysis of these huge volumes of data has become a daunting prospect for researchers entering this field. Here, we review the workflow for typical scRNA-seq data analysis, covering raw data processing and quality control, basic data analysis applicable for almost all scRNA-seq data sets, and advanced data analysis that should be tailored to specific scientific questions. While summarizing the current methods for each analysis step, we also provide an online repository of software and wrapped-up scripts to support the implementation. Recommendations and caveats are pointed out for some specific analysis tasks and approaches. We hope this resource will be helpful to researchers engaging with scRNA-seq, in particular for emerging clinical applications.

MicroRNA binding site variation is enriched in psychiatric disorders.

Psychiatric disorders have a polygenic architecture, often associated with dozens or hundreds of independent genomic loci. Most associated loci impact noncoding regions of the genome, suggesting that the majority of disease heritability originates from the disruption of regulatory sequences. While most research has focused on variants that modify regulatory DNA elements, those affecting cis-acting RNA sequences, such as miRNA binding sites, are also likely to have a significant impact. We intersected genome-wide association study (GWAS) summary statistics with the dbMTS database of predictions for miRNA binding site variants (MBSVs). We compared the distributions of MBSV association statistics to non-MBSVs within brain-expressed 3'UTR regions. We aggregated GWAS p values at the gene, pathway, and miRNA family levels to investigate cellular functions and miRNA families strongly associated with each trait. We performed these analyses in several psychiatric disorders as well as nonpsychiatric traits for comparison. We observed significant enrichment of MBSVs in schizophrenia, depression, bipolar disorder, and anorexia nervosa, particularly in genes targeted by several miRNA families, including miR-335-5p, miR-21-5p/590-5p, miR-361-5p, and miR-557, and a nominally significant association between miR-323b-3p MBSVs and schizophrenia risk. We identified evidence for the association between MBSVs in synaptic gene sets in schizophrenia and bipolar disorder. We also observed a significant association of MBSVs in other complex traits including type 2 diabetes. These observations support the role of miRNA in the pathophysiology of psychiatric disorders and suggest that MBSVs are an important class of regulatory variants that have functional implications for many disorders, as well as other complex human traits.

Evidence of genetic overlap and causal relationships between blood-based biochemical traits and human cortical anatomy.

Psychiatric disorders such as schizophrenia are commonly associated with structural brain alterations affecting the cortex. Recent genetic evidence suggests circulating metabolites and other biochemical traits play a causal role in many psychiatric disorders which could be mediated by changes in the cerebral cortex. Here, we leveraged publicly available genome-wide association study data to explore shared genetic architecture and evidence for causal relationships between a panel of 50 biochemical traits and measures of cortical thickness and surface area. Linkage disequilibrium score regression identified 191 genetically correlated biochemical-cortical trait pairings, with consistent representation of blood cell counts and other biomarkers such as C-reactive protein (CRP), haemoglobin and calcium. Spatially organised patterns of genetic correlation were additionally uncovered upon clustering of region-specific correlation profiles. Interestingly, by employing latent causal variable models, we found strong evidence suggesting CRP and vitamin D exert causal effects on region-specific cortical thickness, with univariable and multivariable Mendelian randomization further supporting a negative causal relationship between serum CRP levels and thickness of the lingual region. Our findings suggest a subset of biochemical traits exhibit shared genetic architecture and potentially causal relationships with cortical structure in functionally distinct regions, which may contribute to alteration of cortical structure in psychiatric disorders.

Pairwise genetic meta-analyses between schizophrenia and substance dependence phenotypes reveals novel association signals with pharmacological significance.

Almost half of individuals diagnosed with schizophrenia also present with a substance use disorder, however, little is known about potential molecular mechanisms underlying this comorbidity. We used genetic analyses to enhance our understanding of the molecular overlap between these conditions. Our analyses revealed a positive genetic correlation between schizophrenia and the following dependence phenotypes: alcohol (rg = 0.368, SE = 0.076, P = 1.61 × 10-6), cannabis use disorder (rg = 0.309, SE = 0.033, P = 1.97 × 10-20) and nicotine (rg = 0.117, SE = 0.043, P = 7.0 × 10-3), as well as drinks per week (rg = 0.087, SE = 0.021, P = 6.36 × 10-5), cigarettes per day (rg = 0.11, SE = 0.024, P = 4.93 × 10-6) and life-time cannabis use (rg = 0.234, SE = 0.029, P = 3.74 × 10-15). We further constructed latent causal variable (LCV) models to test for partial genetic causality and found evidence for a potential causal relationship between alcohol dependence and schizophrenia (GCP = 0.6, SE = 0.22, P = 1.6 × 10-3). This putative causal effect with schizophrenia was not seen using a continuous phenotype of drinks consumed per week, suggesting that distinct molecular mechanisms underlying dependence are involved in the relationship between alcohol and schizophrenia. To localise the specific genetic overlap between schizophrenia and substance use disorders (SUDs), we conducted a gene-based and gene-set pairwise meta-analysis between schizophrenia and each of the four individual substance dependence phenotypes in up to 790,806 individuals. These bivariate meta-analyses identified 44 associations not observed in the individual GWAS, including five shared genes that play a key role in early central nervous system development. The results from this study further supports the existence of underlying shared biology that drives the overlap in substance dependence in schizophrenia, including specific biological systems related to metabolism and neuronal function.

Genetics-informed precision treatment formulation in schizophrenia and bipolar disorder.

Genetically informed drug development and repurposing is an attractive prospect for improving patient outcomes in psychiatry; however, the effectiveness of these endeavors is confounded by heterogeneity. We propose an approach that links interventions implicated by disorder-associated genetic risk, at the population level, to a framework that can target these compounds to individuals. Specifically, results from genome-wide association studies are integrated with expression data to prioritize individual "directional anchor" genes for which the predicted risk-increasing direction of expression could be counteracted by an existing drug. While these compounds represent plausible therapeutic candidates, they are not likely to be equally efficacious for all individuals. To account for this heterogeneity, we constructed polygenic scores restricted to variants annotated to the network of genes that interact with each directional anchor gene. These metrics, which we call a pharmagenic enrichment score (PES), identify individuals with a higher burden of genetic risk, localized in biological processes related to the candidate drug target, to inform precision drug repurposing. We used this approach to investigate schizophrenia and bipolar disorder and reveal several compounds targeting specific directional anchor genes that could be plausibly repurposed. These genetic risk scores, mapped to the networks associated with target genes, revealed biological insights that cannot be observed in undifferentiated genome-wide polygenic risk score (PRS). For example, an enrichment of these partitioned scores in schizophrenia cases with otherwise low PRS. In summary, genetic risk could be used more specifically to direct drug repurposing candidates that target particular genes implicated in psychiatric and other complex disorders.

Polygenic risk for schizophrenia as a moderator of associations between childhood trauma and schizotypy.

Recent evidence shows that genetic and environmental risk factors for psychotic disorders are associated with higher levels of schizotypy (or psychosis proneness) in the general population. However, little is known about how these risk factors interact. We specifically examined whether genetic loading for schizophrenia moderates the association between childhood trauma severity and schizotypy. Schizotypy was measured using the Schizotypal Personality Questionnaire (SPQ), and childhood trauma severity was measured with the Childhood Trauma Questionnaire (CTQ) among a total of 168 participants (comprising 51 healthy individuals, 56 diagnosed with schizophrenia, and 61 with bipolar disorder). Polygenic risk scores (PRS) for schizophrenia were calculated for all participants and examined as a potential moderator of associations between total scores on the CTQ and schizotypy total scores and dimensions (i.e., cognitive-perceptual, interpersonal, disorganised). Multiple linear regression models revealed associations between childhood trauma and all dimensions of schizotypy, but no associations between PRS and schizotypy. A significant interaction between PRS and childhood trauma was evident for the interpersonal and disorganised dimensions of schizotypy, as well as the total score, reflecting positive associations between childhood trauma severity and these two schizotypal dimensions, only for individuals with low or average PRS for schizophrenia. This suggests that trauma may be able to increase risk for psychosis independently of any genetic vulnerability. The present findings are consistent with the idea of several risk pathways for the development of psychotic disorders.