Despite an estimated twin heritability of ~50%, genome-wide association studies (GWAS) of opioid use disorder (OUD) have revealed few genome-wide signi cant (GWS) loci, with replicated ndings only in European-ancestry individuals. To identify novel loci, including those in non-European ancestries, and improve our understanding of the biology of OUD, we conducted a cross-ancestry meta-analysis using the Million Veteran Program (MVP). OUD cases in MVP had at least 1 International Classi cation of Diseases (ICD)-9 or ICD-10 code for opioid abuse or dependence (N=31,473). Opioid-exposed controls (N=394,471) had one or more outpatient opioid prescription lls. We conducted GWAS for each major ancestral group in MVP: African Americans (AAs; N=88,498), European Americans (EAs; N=302,585), and Hispanic Americans (HAs; N=34,861), followed by a cross-ancestry meta-analysis. Ten loci were GWS in the cross-ancestry meta-analysis, 8 of them novel. In addition to the known coding variant rs1799971 in OPRM1, which was the lead SNP genome-wide (p=6.78x10 −10 ), and a recently reported exonic variant in FURIN, we identi ed intronic variants in RABEPK, FBXW4, NCAM1, and KCNN1. Ancestry-speci c analyses identi ed an additional novel locus for each of the 3 ancestry groups. A supplementary meta-analysis within EAs that included MVP and other samples identi ed a locus in TSNARE1, which was also GWS in the cross-ancestry meta-analysis of all datasets. Gene-based association analyses identi ed 1 gene in AAs (CHRM2) and 3 in EAs (OPRM1, DRD2, and FTO). Signi cant genetic correlations (r g 's) were identi ed for 127 traits, including positive correlations with schizophrenia, problematic alcohol use, and major depressive disorder. The most signi cantly enriched cell type group was the central nervous system with gene-expression enrichment identi ed in brain regions previously associated with substance use disorders. With a case sample 50% larger than that of the previous largest GWAS, we identi ed 14 loci for OUD, including 12 novel loci, some of which were ancestry speci c. These ndings increase our understanding of the biological pathways involved in OUD, which can inform preventive, diagnostic, and therapeutic efforts and thereby help to address the opioid epidemic. Revision (ICD-10) diagnosis of OUD and control subjects were opioid exposed. Further details on phenotyping are described below. This GWAS was used for all subsequent downstream analyses.In a supplementary analysis, we performed within-ancestry meta-analyses for AAs and EAs from the MVP, Yale-Penn

Problematic alcohol use (PAU) is a leading cause of death and disability worldwide. To improve our understanding of the genetics of PAU, we conducted a large cross-ancestry meta-analysis of PAU in 1,079,947 individuals. We observed a high degree of cross-ancestral similarity in the genetic architecture of PAU and identified 110 independent risk variants in within- and cross-ancestry analyses. Cross-ancestry fine-mapping improved the identification of likely causal variants. Prioritizing genes through gene expression and/or chromatin interaction in brain tissues identified multiple genes associated with PAU. We identified existing medications for potential pharmacological studies by drug repurposing analysis. Cross-ancestry polygenic risk scores (PRS) showed better performance in independent sample than single-ancestry PRS. Genetic correlations between PAU and other traits were observed in multiple ancestries, with other substance use traits having the highest correlations. The analysis of diverse ancestries contributed significantly to the findings, and fills an important gap in the literature.

Childhood trauma (CT) is well established as a potent risk factor for the development of mental disorders. However, the potential of adverse early experiences to exert chronic and profound effects on physical health, including aberrant metabolic phenotypes, has only been more recently explored. Among these consequences is metabolic syndrome (MetS), which is characterised by at least three of five related cardiometabolic traits: hypertension, insulin resistance/hyperglycaemia, raised triglycerides, low high-density lipoprotein and central obesity. The deleterious effects of CT on health outcomes may be partially attributable to dysregulation of the hypothalamicpituitary-adrenal (HPA) axis, which coordinates the response to stress, and the consequent fostering of a pro-inflammatory environment. Epigenetic tags, such as DNA methylation, which are sensitive to environmental

Despite an estimated twin heritability of ~50%, genome-wide association studies (GWAS) of opioid use disorder (OUD) have revealed few genome-wide significant (GWS) loci, with replicated findings only in European-ancestry individuals. To identify novel loci, including those in non-European ancestries, and improve our understanding of the biology of OUD, we conducted a cross-ancestry meta-analysis using the Million Veteran Program (MVP). OUD cases in MVP had at least 1 International Classification of Diseases (ICD)-9 or ICD-10 code for opioid abuse or dependence (N=31,473). Opioid-exposed controls (N=394,471) had one or more outpatient opioid prescription fills. We conducted GWAS for each major ancestral group in MVP: African Americans (AAs; N=88,498), European Americans (EAs; N=302,585), and Hispanic Americans (HAs; N=34,861), followed by a cross-ancestry meta-analysis. Ten loci were GWS in the cross-ancestry meta-analysis, 8 of them novel. In addition to the known coding variant rs1799971 in OPRM1, which was the lead SNP genome-wide (p=6.78x10-10), and a recently reported exonic variant in FURIN, we identified intronic variants in RABEPK, FBXW4, NCAM1, and KCNN1. Ancestry-specific analyses identified an additional novel locus for each of the 3 ancestry groups. A supplementary meta-analysis within EAs that included MVP and other samples identified a locus in TSNARE1, which was also GWS in the cross-ancestry meta-analysis of all datasets. Gene-based association analyses identified 1 gene in AAs (CHRM2) and 3 in EAs (OPRM1, DRD2, and FTO). Significant genetic correlations (rg's) were identified for 127 traits, including positive correlations with schizophrenia, problematic alcohol use, and major depressive disorder. The most significantly enriched cell type group was the central nervous system with gene-expression enrichment identified in brain regions previously associated with substance use disorders. With a case sample 50% larger than that of the previous largest GWAS, we identified 14 loci for OUD, including 12 novel loci, some of which were ancestry specific. These findings increase our understanding of the biological pathways involved in OUD, which can inform preventive, diagnostic, and therapeutic efforts and thereby help to address the opioid epidemic.