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Original Investigation
June 3, 2020

Association of OPRM1 Functional Coding Variant With Opioid Use Disorder: A Genome-Wide Association Study

Author Affiliations
  • 1Department of Psychiatry, Yale School of Medicine, New Haven, Connecticut
  • 2Department of Psychiatry, Veterans Affairs Connecticut Healthcare System, West Haven
  • 3Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut
  • 4Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, United Kingdom
  • 5Department of Genetics, University of Pennsylvania Perelman School of Medicine, Philadelphia
  • 6Crescenz Veterans Affairs Medical Center, Philadelphia, Pennsylvania
  • 7Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, Massachusetts
  • 8Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts
  • 9Department of Epidemiology, Boston University School of Public Health, Boston, Massachusetts
  • 10Department of Neurology, Boston University School of Medicine, Boston, Massachusetts
  • 11Department of Ophthalmology, Boston University School of Medicine, Boston, Massachusetts
  • 12Yale School of Public Health, New Haven, Connecticut
  • 13Department of Psychiatry, University of Pennsylvania Perelman School of Medicine, Philadelphia
  • 14Department of Genetics, Yale University School of Medicine, New Haven, Connecticut
  • 15Department of Neuroscience, Yale University School of Medicine, New Haven, Connecticut
JAMA Psychiatry. Published online June 3, 2020. doi:10.1001/jamapsychiatry.2020.1206
Key Points

Question  What is the genetic architecture of opioid use disorder, and how is it associated with other traits?

Findings  In this genome-wide association study, meta-analysis of 10 544 individuals of European ancestry with opioid use disorder and 72 163 opioid-exposed control individuals identified OPRM1 functional variant rs1799971 as associated with opioid use disorder, with replication in 2 independent samples; no significant associations were detected for individuals of African ancestry (n = 32 088). Opioid use disorder was genetically correlated with 83 traits, including risk of tobacco smoking, depression, neuroticism, worry neuroticism subcluster, and cognitive performance.

Meaning  This genome-wide association study identified a significant genetic variant as associated with opioid use disorder, with replication.

Abstract

Importance  With the current opioid crisis, it is important to improve understanding of the biological mechanisms of opioid use disorder (OUD).

Objectives  To detect genetic risk variants for OUD and determine genetic correlations and causal association with OUD and other traits.

Design, Setting, and Participants  A genome-wide association study of electronic health record–defined OUD in the Million Veteran Program sample was conducted, comprising 8529 affected European American individuals and 71 200 opioid-exposed European American controls (defined by electronic health record trajectory analysis) and 4032 affected African American individuals and 26 029 opioid-exposed African American controls. Participants were enrolled from January 10, 2011, to May 21, 2018, with electronic health record data for OUD diagnosis from October 1, 1999, to February 7, 2018. Million Veteran Program results and additional OUD case-control genome-wide association study results from the Yale-Penn and Study of Addiction: Genetics and Environment samples were meta-analyzed (total numbers: European American individuals, 10 544 OUD cases and 72 163 opioid-exposed controls; African American individuals, 5212 cases and 26 876 controls). Data on Yale-Penn participants were collected from February 14, 1999, to April 1, 2017, and data on Study of Addiction: Genetics and Environment participants were collected from 1990 to 2007. The key result was replicated in 2 independent cohorts: proxy-phenotype buprenorphine treatment in the UK Biobank and newly genotyped Yale-Penn participants. Genetic correlations between OUD and other traits were tested, and mendelian randomization analysis was conducted to identify potential causal associations.

Main Outcomes and Measures  Main outcomes were International Classification of Diseases, Ninth Revision–diagnosed OUD or International Statistical Classification of Diseases and Related Health Problems, Tenth Revision–diagnosed OUD (Million Veteran Program), and DSM-IV–defined opioid dependence (Yale-Penn and Study of Addiction: Genetics and Environment).

Results  A total of 114 759 individuals (101 016 men [88%]; mean [SD] age, 60.1 [12.8] years) were included. In 82 707 European American individuals, a functional coding variant (rs1799971, encoding Asn40Asp) in OPRM1 (μ-opioid receptor gene, the main biological target for opioid drugs; OMIM 600018) reached genome-wide significance (G allele: mean [SE], β = −0.066 [0.012]; P = 1.51 × 10−8). The finding was replicated in 2 independent samples. Mean (SE) single-nucleotide polymorphism–based heritability of OUD was 11.3% (1.8%). Opioid use disorder was genetically correlated with 83 traits, including multiple substance use traits, psychiatric illnesses, cognitive performance, and others. Mendelian randomization analysis revealed the following associations with OUD: risk of tobacco smoking, depression, neuroticism, worry neuroticism subcluster, and cognitive performance. No genome-wide significant association was detected for African American individuals or in transpopulation meta-analysis.

Conclusions and Relevance  This genome-wide meta-analysis identified a significant association of OUD with an OPRM1 variant, which was replicated in 2 independent samples. Post–genome-wide association study analysis revealed associated pleiotropic characteristics. Recruitment of additional individuals with OUD for future studies—especially those of non-European ancestry—is a crucial next step in identifying additional significant risk loci.

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