Cross-ancestry meta-analysis of opioid use disorder uncovers novel loci with predominant effects on brain

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 (rgs) 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.