Genome-wide association study in individuals of European and African ancestry and multi-trait analysis of opioid use disorder identifies 19 independent genome-wide significant risk loci
Year: 2022
Type: article
Study design: Observational Study
Abstract: Background Despite the large toll of opioid use disorder (OUD), genome-wide association studies (GWAS) of OUD to date have yielded few susceptibility loci. Methods We performed a large-scale GWAS of OUD in individuals of European (EUR) and African (AFR) ancestry, optimizing genetic informativeness by performing MTAG (Multi-trait analysis of GWAS) with genetically correlated substance use disorders (SUDs). Meta-analysis included seven cohorts: the Million Veteran Program (MVP), Psychiatric Genomics Consortium (PGC), iPSYCH, FinnGen, Partners Biobank, BioVU, and Yale-Penn 3, resulting in a total N=639,709 (N cases =20,858) across ancestries. OUD cases were defined as having lifetime OUD diagnosis, and controls as anyone not known to meet OUD criteria. We estimated SNP-heritability (h 2 SNP ) and genetic correlations (r g ). Based on genetic correlation, we performed MTAG on OUD, alcohol use disorder (AUD), and cannabis use disorder (CanUD). Results The EUR meta-analysis identified three genome-wide significant (GWS; p ≤5×10 −8 ) lead SNPs—one at FURIN (rs11372849; p =9.54×10 −10 ) and two OPRM1 variants (rs1799971, p =4.92×10 −09 ; rs79704991, p =1.37×10 −08 ; r 2 =0.02). Rs1799971 ( p =4.91×10 −08 ) and another OPRM1 variant (rs9478500; p =1.95×10 −8 ; r 2 =0.03) were identified in the cross-ancestry meta-analysis. Estimated h 2 SNP was 12.75%, with strong r g with CanUD (r g =0.82; p =1.14×10 −47 ) and AUD (r g =0.77; p =6.36×10 −78 ). The OUD-MTAG resulted in 18 GWS loci, some of which map to genes or gene regions that have previously been associated with psychiatric or addiction phenotypes. Conclusions We identified multiple OUD variant associations at OPRM1 , single variant associations with FURIN , and 18 GWS associations in the OUD-MTAG. OUD is likely influenced by both OUD-specific loci and loci shared across SUDs.
Source: Molecular Psychiatry
Authors: Joseph D. Deak, Hang Zhou, Marco Galimberti, Daniel F. Levey, Frank R. Wendt, Sandra Sanchez-Roige, Alexander S. Hatoum, Emma C. Johnson, Yaira Z. Nunez, Ditte Demontis, Anders D. Børglum, Veera M. Rajagopal, Mariela V. Jennings, Rachel L. Kember, Amy C. Justice, Howard J. Edenberg, Arpana Agrawal, Renato Polimanti, Henry R. Kranzler, Joel Gelernter
Institutions: Yale University, VA Connecticut Healthcare System, University of California San Diego, Vanderbilt University Medical Center, Washington University in St. Louis, Aarhus University, Lundbeck Foundation, Philadelphia VA Medical Center, University of Pennsylvania, Indiana University School of Medicine
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $4,790
Funders: U.S. Department of Health and Human Services, U.S. Department of Veterans Affairs, Brain Research Foundation, Tobacco-Related Disease Research Program, Office of Research and Development, Aarhus Universitet, Lundbeckfonden, Novo Nordisk, Novo Nordisk Fonden, H. Lundbeck A/S, National Institutes of Health, National Institute on Alcohol Abuse and Alcoholism, National Institute of Mental Health, National Institute on Drug Abuse, National Center for Advancing Translational Sciences
Awards: 5/7 Psychiatric Genomics Consortium: Finding actionable variation, G122833759, G1278019779, G1482489452, G1644766664, G1662605755, G1808297124, G214445032, G2499984794, G2719215791, G2905247291, G2924140200, Characterizing the phenotypic spectrum associated with genetic liability for alcohol use disorder, G3246699782, Genetics of Alcohol Dependence in African Americans: Recruitment, 2/6 COMpAAAS U01: Observation Study, G3452148273, G347670469, G36232875, G3987400284, 5/6 COMpAAAS U24: Resource in Informatics and Biostatistics (RIB), A Big Data Approach to Identify Epigenetic, Transcriptomic, and Network Dynamics as Immune Dysfunction Drivers Associated with HIV Infection and Substance Use Disorder, G4418003357, G4814458579, Alcohol Associated Outcomes Among HIV+/- Aging Veterans, G5497799976, G5574319837, G5732555730, 1/6 COMpAAAS U24: Coordinating Center, G6305174853, Investigating the Systems Genetics of the Patterns of Polysubstance Abuse and Addiction, Translational Alcohol Research Program (TARP), G6742998398, DELINEATING THE ROLE OF GENETIC INFLUENCES ON CANNABIS INVOLVEMENT, G684320456, Decoding the Sex-Specific Biological Mechanisms of Psychiatric Disorders Using Genome-Wide Analyses, G768810160, G8029522133, G8148256879, G833165568, G84716273, G8629591451, 7/7 Psychiatric Genomics Consortium: Advancing Discovery and Impact, Building Bridges to Allow Cross-species Translational genetics for the Study of Addiction, Yale Clinical and Translational Science Award
OpenAlex ID: W4287147673