GWAS including 82,707 subjects identifies functional coding variant in OPRM1 gene associated with opioid use disorder

One way to address the current crisis in opioid use is to improve our understanding of the biological mechanisms of opioid use disorder (OUD). We completed a primary GWAS of electronic health record-defined OUD in European-ancestry participants in the Million Veteran Program (MVP) sample, which included 8,529 affected subjects and 71,200 opioid-exposed controls. In the MVP alone, there were no genome-wide significant (GWS) associations. We then subjected the MVP and additional OUD GWAS results from the Yale-Penn and SAGE samples to meta-analysis (in total, 10,544 OUD cases and 72,163 opioid-exposed controls). A functional coding variant (rs1799971, encoding Asn40Asp) in OPRM1 (mu opioid receptor gene, the main biological target for opioid drugs) reached GWS (p=1.51x10-8); then replicated in two independent samples (each at p<0.05). The final meta-analyzed p-value for this variant in all samples was 7.81x10-10. SNP-based heritability of OUD was 11.3%. OUD was genetically correlated with 83 traits, including multiple substance use traits, psychiatric illnesses, cognitive performance, and others. Mendelian Randomization revealed possible causal effects on OUD risk from tobacco smoking, major depression, neuroticism, and cognitive performance. Despite the inclusion of data from the MVP, discovery of a significant association depended on including other purpose-collected samples as well. Recruitment of additional opioid dependent subjects for future studies - especially of non-European ancestry - is a crucial next step.