A total of 110 variants were associated with PAU in either within-ancestry or cross-ancestry analyses. These include rs1799971 in OPRM1 that encodes the μ opioid receptor, which plays roles in regulating pain, reward and addictive behaviors. This variant was also associated with OUD on multiple large GWAS40,42. Previously, there were inconsistent candidate gene association results for OPRM1*rs1799971 and AUD (reviewed in ref. 43). This is the first GWAS to confirm the association of rs1799971 in PAU; the risk allele is the same as for OUD. In contrast to an apparent EUR-specific effect of rs1799971 on OUD, the OPRM1 association with PAU (P = 6.16 × 10−9) was detected in the cross-ancestry meta-analysis. Further investigation in larger non-EUR samples is needed to assess the association of this SNP with SUDs in different population groups. Rs6265 in brain-derived neurotrophic factor (BDNF) encodes a member of the nerve growth factor family of proteins and has been investigated intensively in the past decades44; studies showed that this variant is associated with smoking traits11 and externalizing behavior45. Rs13107325 in solute carrier family 39 member 8 (SLC39A8) has been associated with schizophrenia46, substance use10,11 and many glycemic traits, and is critical for glycosylation pathways47.
