Genome‐wide scan identifies opioid overdose risk locus close to MCOLN1

The United States is experiencing the worst opioid overdose (OpOD) crisis in its history. We carried out a genome‐wide association study on OpOD severity among 3 477 opioid‐exposed individuals, 1 019 of whom experienced OpODs, including 2 032 European Americans (EAs) (653 overdose cases), and 1 445 African Americans (AAs) (366 overdose cases). Participants were scored 1 to 4 based on their reported overdose status and the number of times that medical treatment was required. Genome‐wide association study (GWAS) of EAs and AAs separately resulted in two genome‐wide significant (GWS) signals in AAs but none in EAs. The first signal was represented by three closely mapped variants (rs115208233, rs116181528, and rs114077267) located near mucolipin 1 (MCOLN1) and patatin‐like phospholipase domain containing 6 (PNPLA6), and the other signal was represented by rs369098800 near dead‐box helicase 18 (DDX18). There were no additional GWS signals in the trans‐population meta‐analysis, so that post‐GWAS analysis focused on these loci. In network analysis, MCOLN1 was coexpressed with PNPLA6, but only MCOLN1‐associated genes were enriched in functional categories relevant to OpOD, including calcium and cation channel activities; no enrichment was observed for PNPLA6‐associated genes. Drug repositioning analysis was carried out in the connectivity map (CMap) database for MCOLN1 (PNPLA6 was not available in CMap) and showed that the opioid agonist drug‐induced expression profile is similar to that of MCOLN1 overexpression and yielded the highest‐ranked expression profile of 83 drug classes. Thus, MCOLN1 may be a risk gene for OpOD, but replication is needed. This knowledge could be helpful in the identification of drug targets for preventing OpOD. Opioid overdose deaths are at a high level in the United States. To improve our understanding of the biology and genetics of risk for opioid overdose, we carried out a genomewide association study of opioid overdose in European‐ and African‐Americans and identified markers near the gene MCOLN1 as associated with opioid overdose in African‐Americans but not European‐Americans. Post‐GWAS analyses showed that the profile of MCOLN1 overexpression is similar to the expression profiles of many opioid agonists, providing further support for MCOLN1 as a risk gene for opioid overdose.