For opioids, six GWAS have been reported. Three SNP-based GWAS were small (N<1,000), and no SNPs attained genome-wide significance [106–108]. The three larger GWAS, including two SNP-based [109, 110] and one copy number variant-based [111], each found genome-wide significant associations in different genetic loci, but these association signals all await independent replication. GWAS analyses have not yielded genome-wide significant evidence for any of the biologically plausible opioid receptor genes. However, such evidence emerged from a targeted study of cis-eQTL SNPs of the μ-opioid receptor gene (OPRM1); smallest P=4.3×10−8 for intronic SNP rs3778150 with total N=16,729 of European or African American ancestry [112]. Much attention has focused on OPRM1 SNP associations but with inconclusive findings from mostly studies of single cohorts. The OPRM1 SNP rs1799971, which results in an amino acid change in the μ-opioid receptor, has been the most extensively studied. In an accumulation of evidence for rs1799971, meta-analysis of >28,000 European ancestry participants from 25 studies supported a modest association with general substance dependence, rather than opioids or any substance specifically [113]. As we previously reported, the cis-eQTL SNP
