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.