In this study, we leveraged gSEM across new and existing OA GWAS that employed various opioid-related phenotypes to conduct the largest EA-focused GWAS to date. Our results show the strongest statistical evidence to date for an association between variants in intron 1 of OPRM1 with OA. Conflicting results from variant conditional analysis and haplotype analysis of the GWS variants and previously associated rs1799971 (A118G) indicate that further functional study of intron 1 variants will be needed to determine the causal variant(s) driving this association with OA. Gene-based analyses identified two GWS associations: PPP6C and FURIN. These genes are novel for OA, however, variants within them have been associated at genome-wide significance with related phenotypes, such as cigarette smoking, alcohol consumption, general risk taking, and schizophrenia. With strong SNP-based heritability for these OA phenotypes, but only these few GWS findings, it is clear that increased sample sizes for GWAS and complementary approaches (e.g., gene regulation in postmortem brain tissues) are needed to identify much of the genetics driving risk of OA as well as to extend these studies to non-European ancestries.
