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

Abstract

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 (rg = 0.64, 0.80, respectively). We also identified numerous additional genetic correlations with POU, including alcohol dependence (rg = 0.74), smoking initiation (rg = 0.63), pain relief medication intake (rg = 0.49), major depressive disorder (rg = 0.44), chronic pain (rg = 0.42), insomnia (rg = 0.39), and loneliness (rg = 0.28). Although POU was positively genetically correlated with risk-taking (rg = 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.

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

“…Consistent with prior ndings, OUD showed strong genetic correlations with multiple substance use disorders, psychiatric disorders, cognitive traits, and risk behavior 13,15,16,63 . Mendelian randomization analyses demonstrated causal effects of OUD on problematic alcohol use and cannabis use disorder, and a bidirectional causal effect of drinks per week.…”

“…Although these traits are known to be genetically correlated, it is unknown whether there is a shared genetic structure between OUD, other substance use, and psychiatric disorders. Negative r g 's were seen for educational attainment 13,15,16 , cognitive performance 13 and subjective wellbeing 16 . Causal effects on OUD for some of these traits were identi ed via Mendelian randomization (MR) analysis.…”

“…These studies also identi ed signi cant genetic correlations (r g 's) with traits well known to co-occur with OUD, suggesting widespread pleiotropy. The strongest positive r g 's were with substance-related traits (e.g., alcohol dependence/use disorder, cannabis use disorder, drinks/week, cigarettes/day) 12,13,15,16 , and psychiatric disorders (e.g., attention de cit hyperactivity disorder (ADHD), posttraumatic stress disorder (PTSD), major depressive disorder (MDD), schizophrenia, bipolar disorder, neuroticism) 13,15,16 . Although these traits are known to be genetically correlated, it is unknown whether there is a shared genetic structure between OUD, other substance use, and psychiatric disorders.…”

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

“…Two recent GWAS have increased sample sizes for genetic discovery by examining opioid-related phenotypes other than OUD. A GWAS of prescription opioid misuse in an EA sample from 23andMe (27,805 cases) identified 2 novel GWS loci 15 . A meta-analysis of European-ancestry individuals included 23,367 cases ascertained using either Diagnostic and Statistical Manual of Mental Disorders diagnoses (DSM) or frequency of opioid use (FOU) and 384,629 controls 16 .…”

“…These studies also identified significant genetic correlations (r g 's) with traits well known to co-occur with OUD, suggesting widespread pleiotropy. The strongest positive r g 's were with substance-related traits (e.g., alcohol dependence/use disorder, cannabis use disorder, drinks/week, cigarettes/day) 12,13,15,16 , and psychiatric disorders (e.g., attention deficit hyperactivity disorder (ADHD), posttraumatic stress disorder (PTSD), major depressive disorder (MDD), schizophrenia, bipolar disorder, neuroticism) 13,15,16 . Although these traits are known to be genetically correlated, it is unknown whether there is a shared genetic structure between OUD, other substance use, and psychiatric disorders.…”