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

Sandra Sanchez‐Roige ,Nadia K Litterman,Steven J Pitts,Catherine H Wilson,Robert K Bell,Vladimir Vacic,Suyash Shringarpure,Carrie A M Northover,Elizabeth S Noblin,Matthew H Mcintyre,Michelle Agee,Olga V Sazonova,Nicholas A Furlotte,Aaron Kleinman,David A Hinds,Katarzyna Bryc,Chao Tian,Jennifer C Mccreight,J Fah Sathirapongsasuti,Joyce Y Tung,Adam Auton,Babak Alipanahi,Janie F Shelton,Karen E Huber,Joanna L Mountain,Mariela Jennings ,Julia Sealock,Pierre Fontanillas,Alexander S Hatoum,Yuye Huang,Lea K Davis,Sarah L Elson,Sevim B Bianchi ,Abraham A Palmer

doi:10.1038/s41380-021-01335-3

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.

Highlights

Opioid use disorders (OUD) represent a global epidemic [1]
In this study, we performed a genome-wide association study (GWAS) of problematic opioid use (‘ever taking prescription painkillers not as prescribed’) in 132,113 23andMe research participants of European ancestry. This represented a novel approach to studying OUD in a population-based cohort
Our results show that this single question captured a genetic signal that is correlated with signals from well-characterized cohorts that have been clinically diagnosed with OUD

Summary

Introduction

Opioid use disorders (OUD) represent a global epidemic [1]. Every day, 128 people in the United States die after overdosing on opiates. The pathway to opiate addiction has changed over the last few decades. In the 1960s, more than 80% of people who began using opioids initiated with heroin [2]; by 2013, nearly 80% of opioid users reported that their first regular opioid was a prescription pain reliever [3]. The misuse of and addiction to opiates—including prescription pain relievers, heroin, and synthetic opioids such as fentanyl—is a serious emergency that affects public health as well as social and economic welfare. The COVID-19 pandemic made it increasingly difficult for individuals with OUD to access treatment and impacted mental health, triggering both initial and continued use of opioids [4], which is likely to further increase rates of OUD [5]

Methods

Results

Conclusion