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Meta-Analysis
. 2022 Oct;27(10):3970-3979.
doi: 10.1038/s41380-022-01709-1. Epub 2022 Jul 25.

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

Joseph D Deak  1   2 , Hang Zhou  1   2 , Marco Galimberti  1   2 , Daniel F Levey  1   2 , Frank R Wendt  1   2 , Sandra Sanchez-Roige  3   4 , Alexander S Hatoum  5 , Emma C Johnson  5 , Yaira Z Nunez  1   2 , Ditte Demontis  6   7   8 , Anders D Børglum  6   7   8 , Veera M Rajagopal  6   7   8 , Mariela V Jennings  3 , Rachel L Kember  9   10 , Amy C Justice  1   2 , Howard J Edenberg  11 , Arpana Agrawal  5 , Renato Polimanti  1   2 , Henry R Kranzler  9   10 , Joel Gelernter  12   13
Affiliations
Meta-Analysis

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

Joseph D Deak et al. Mol Psychiatry. 2022 Oct.

Abstract

Despite the large toll of opioid use disorder (OUD), genome-wide association studies (GWAS) of OUD to date have yielded few susceptibility loci. 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, Psychiatric Genomics Consortium, iPSYCH, FinnGen, Partners Biobank, BioVU, and Yale-Penn 3, resulting in a total N = 639,063 (Ncases = 20,686;Neffective = 77,026) across ancestries. OUD cases were defined as having a lifetime OUD diagnosis, and controls as anyone not known to meet OUD criteria. We estimated SNP-heritability (h2SNP) and genetic correlations (rg). Based on genetic correlation, we performed MTAG on OUD, alcohol use disorder (AUD), and cannabis use disorder (CanUD). A leave-one-out polygenic risk score (PRS) analysis was performed to compare OUD and OUD-MTAG PRS as predictors of OUD case status in Yale-Penn 3. 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 = 1.11 × 10-08; r2 = 0.02). Rs1799971 (p = 4.91 × 10-08) and another OPRM1 variant (rs9478500; p = 1.95 × 10-08; r2 = 0.03) were identified in the cross-ancestry meta-analysis. Estimated h2SNP was 12.75%, with strong rg with CanUD (rg = 0.82; p = 1.14 × 10-47) and AUD (rg = 0.77; p = 6.36 × 10-78). The OUD-MTAG resulted in a GWAS Nequivalent = 128,748 and 18 independent GWS loci, some mapping to genes or gene regions that have previously been associated with psychiatric or addiction phenotypes. The OUD-MTAG PRS accounted for 3.81% of OUD variance (beta = 0.61;s.e. = 0.066; p = 2.00 × 10-16) compared to 2.41% (beta = 0.45; s.e. = 0.058; p = 2.90 × 10-13) explained by the OUD PRS. The current study identified OUD variant associations at OPRM1, single variant associations with FURIN, and 18 GWS associations in the OUD-MTAG. The genetic architecture of OUD is likely influenced by both OUD-specific loci and loci shared across SUDs.

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Conflict of interest statement

HRK is a member of scientific advisory boards for Dicerna Pharmaceuticals, Sophrosyne Pharmaceuticals, and Enthion Pharmaceuticals; a consultant to Sophrosyne Pharmaceuticals; and a member of the American Society of Clinical Psychopharmacology’s Alcohol Clinical Trials Initiative, which during the past three years was supported by Alkermes, Dicerna, Ethypharm, Lundbeck, Mitsubishi, and Otsuka. HRK and JG are named as inventors on PCT patent application #15/878,640 entitled: “Genotype-guided dosing of opioid agonists,” filed January 24, 2018 and issued on January 26, 2021 as U.S. Patent No. 10,900,082. JG and RP were paid for editorial work for the journal “Complex Psychiatry.” All other authors report no biomedical financial interests or potential conflicts of interest.

Figures

Fig. 1
Fig. 1. Summary of OUD GWAS, meta-analysis, and MTAG study design.
Overview of European-ancestry opioid use disorder (OUD) genome-wide association study and OUD multi-trait analysis.
Fig. 2
Fig. 2. OUD and OUD-MTAG manhattan plots.
Manhattan plots of (A) European-ancestry OUD GWAS results and (B) OUD-MTAG multi-trait GWAS results.
Fig. 3
Fig. 3. OUD genetic correlation results.
EUR OUD GWAS genetic correlations (rg) with mental health, pain, physical health, sociodemographic, and substance use traits of interest.
See this image and copyright information in PMC

References

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