Genome-wide association study of problematic opioid prescription use in 132,113 23andMe research participants of European ancestry

The growing prevalence of opioid use disorder (OUD) constitutes an urgent health crisis. Ample evidence indicates that risk for OUD is heritable. As a surrogate (or proxy) for OUD, we explored the genetic basis of using prescription opioids 'not as prescribed'. We hypothesized that misuse of opiates might be a heritable risk factor for OUD. To test this hypothesis, we performed a genome-wide association study (GWAS) of problematic opioid use (POU) in 23andMe research participants of European ancestry (N = 132,113; 21% cases). We identified two genome-wide significant loci (rs3791033, an intronic variant of KDM4A; rs640561, an intergenic variant near LRRIQ3). POU showed positive genetic correlations with the two largest available GWAS of OUD and opioid dependence (r_g = 0.64, 0.80, respectively). We also identified numerous additional genetic correlations with POU, including alcohol dependence (r_g = 0.74), smoking initiation (r_g = 0.63), pain relief medication intake (r_g = 0.49), major depressive disorder (r_g = 0.44), chronic pain (r_g = 0.42), insomnia (r_g = 0.39), and loneliness (r_g = 0.28). Although POU was positively genetically correlated with risk-taking (r_g = 0.38), conditioning POU on risk-taking did not substantially alter the magnitude or direction of these genetic correlations, suggesting that POU does not simply reflect a genetic tendency towards risky behavior. Lastly, we performed phenome- and lab-wide association analyses, which uncovered additional phenotypes that were associated with POU, including respiratory failure, insomnia, ischemic heart disease, and metabolic and blood-related biomarkers. We conclude that opioid misuse can be measured in population-based cohorts and provides a cost-effective complementary strategy for understanding the genetic basis of OUD.