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Deak JD, Zhou H, Galimberti M, Levey DF, Wendt FR, Sanchez-Roige S, Hatoum AS, Johnson EC, Nunez YZ, Demontis D, Børglum AD, Rajagopal VM, Jennings MV, Kember RL, Justice AC, Edenberg HJ, Agrawal A, Polimanti R, Kranzler HR, Gelernter J. 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. Molecular Psychiatry. 2022 Oct 1; 27(10):3970-3979.
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 (N? = 20,686;N? = 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 (h) and genetic correlations (r). 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) lead SNPs-one at FURIN (rs11372849; p? = 9.54?×?10) and two OPRM1 variants (rs1799971, p? = 4.92?×?10; rs79704991, p? = 1.11?×?10; r? = 0.02). Rs1799971 (p? = 4.91?×?10) and another OPRM1 variant (rs9478500; p? = 1.95?×?10; r? = 0.03) were identified in the cross-ancestry meta-analysis. Estimated h was 12.75%, with strong r with CanUD (r? = 0.82; p? = 1.14?×?10) and AUD (r? = 0.77; p? = 6.36?×?10). The OUD-MTAG resulted in a GWAS N? = 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) compared to 2.41% (beta? = 0.45; s.e.? = 0.058; p? = 2.90?×?10) 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.