Genome-wide association study and multi-trait analysis of opioid use disorder identifies novel associations in 639,709 individuals of European and African ancestry

Abstract

BackgroundDespite the large toll of opioid use disorder (OUD), genome-wide association studies (GWAS) of OUD to date have yielded few susceptibility loci.MethodsWe 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 (Ncases=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 (h2SNP) and genetic correlations (rg). Based on genetic correlation, we performed MTAG on OUD, alcohol use disorder (AUD), and cannabis use disorder (CanUD).ResultsThe 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; r2=0.02). Rs1799971 (p=4.91×10−08) and another OPRM1 variant (rs9478500; p=1.95×10−8; 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 18 GWS loci, all of which map to genes or gene regions that have previously been associated with psychiatric or addiction phenotypes.ConclusionsWe 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.

Multi-trait Analysis of GWAS (MTAG) of Substance Use Traits Identifies Novel Genetic Loci and Phenomic Associations

“…Of the variants in common between that MTAG analysis and the present analysis, we also observed association with 14 of the 45 SNPs in our MTAG-AUD results. In our MTAG-OUD analysis, we also replicated six of the nine variants in common with a recent OUD MTAG analysis of OUD, CUD and AUD 10 . Although OPRM1 was not significantly associated in the prior MTAG, our MTAG-OUD analyses identified the OPRM1 SNP rs1799971 as a lead variant, potentially due to our inclusion of the smoking initiation GWAS or the larger input OUD GWAS sample in our analysis.…”

“…were GWS in at least one of the other of the three SUT GWAS used for MTAG, and 30 were GWS in other GWAS of SUTs, not limited to the GWAS included in this study. Variants including exonic SNPs in OPRM1 (rs1799971, p = 7.52 x 10 -9 ) and FURIN (rs4702, p = 3.29 x 10 -12 ) have been shown to be GWS in previous OUD GWAS 3,10 . Five GWS loci are novel with no prior associations found with OUD or any SUT.…”

“…In a meta-analysis of problematic alcohol use (PAU) 9 , MTAG analysis of PAU and a measure of weekly alcohol consumption 7 increased the number of independent loci for PAU from 29 to 76. MTAG analysis of OUD with AUD and CUD 10 increased the number of GWS loci for OUD to 18 from 3 in the initial GWAS meta-analysis. Because MTAG for multiple, genetically correlated SUTs yields greater statistical and interpretive power than individual trait GWAS, the availability of large GWAS of alcohol- and smoking-related traits could enhance findings from GWAS of traits with smaller accumulated samples (e.g., CUD and OUD).…”

Substance use and common contributors to morbidity: A genetics perspective

“…Well-powered GWASs of substance use and SUDs are now available for alcohol, nicotine, cannabis and opioids. 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 , 92 , 93 , 94 , 95 Beyond identification of associated variants, well-powered GWAS have mobilized a suite of analytic paradigms aimed at studying genetic sources of comorbidity - Figure 1 illustrates these specific approaches.…”

“…As expected, pain conditions have been associated with genetic liability for OUD and opioid cessation. 84,85,87,108,109 However, these associations also extend to other substances (tobacco, alcohol, general SUD). 85,89,110 A plausible mechanism underlying these associations may be explained by reward mechanisms that substances (particularly, opioids) act upon.…”