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

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.

Multi-trait genome-wide association analyses leveraging alcohol use disorder findings identify novel loci for smoking behaviors in the Million Veteran Program

“…For such SNPs, MTAG could have false positives in the first trait [14]. This statement is consistent with a recent study on opioid use disorder, which showed that increased detection of MTAG might come with the loss of specificity [16]. In our analyses, some of the newly identified loci by MTAG were verified to be shared between AUD and smoking behaviors by colocalization, such as rs6589386 on DRD2.…”

“…For example, Wu et al utilized a sample size of approximately 60,000 EA individuals and identified genetic variants on seven genes commonly associated with four out of the following five psychiatric disorders: schizophrenia, bipolar disorder, autism spectrum disorder, attention-deficit hyperactivity disorder, and depression [15]. Recently, Deak et al applied MTAG to discover novel risk loci for opioid use disorder [16], and Xu et al applied MTAG for four common substance use disorders and reported several novel loci for opioid use disorder, cannabis use disorder, alcohol and smoking behaviors [17]. These studies show that MTAG is a useful method for identifying loci associated with strongly correlated psychiatric disorders, including substance use behaviors.…”

Genome-wide analyses reveal novel opioid use disorder loci and genetic overlap with schizophrenia, bipolar disorder, and major depression

“…Finally, no lead variants in the shared loci for OUD and psychiatric disorders, had a p-value <0.05 in the independent AA GWAS dataset on OUD 21 . A total of four of the OUD risk loci identified by conjFDR were identified in recent larger GWAS on OUD, specifically the PPP6C 42 , NCAM1 39 , DRD2 39 and FURIN 39,42,43 loci, supporting the validity of the results.…”

“…It has previously been associated with SCZ 40 , BD 27 and MD 41 . This locus was not identified in the original OUD GWAS 21 , but reached genome-wide significance in subsequent GWAS on OUD, validating this finding 39,42,43 . The lead SNP rs4702 is shown to influence the expression of its nearest gene FURIN in neurons derived from human induced pluripotent stem cells, and influence synaptic function in synergy with other SCZ risk variants 50 .…”

“…We identified another OUD risk locus on chromosome 11 which was shared with both BD and MD. The locus is novel for BD and has previously been implicated in OUD 43 , MD 41 , as well as for alcohol use disorder 54 and SCZ 40 .The nearest gene to the lead SNP is DRD2 , while the most likely causal genes according to the V2G algorithm was ANKK1 and TTC12 . The gene cluster TTC12-ANKK1-DRD2-NCAM1 (NTAD) have previously been widely linked to nicotine 55 , alcohol 56 and other drug dependencies 57 .…”