To enhance the detection of replicable OPRM1 SNP associations with heroin addiction, our study focused only on SNPs with evidence for altering OPRM1 mRNA expression in human brain, thereby reducing the multiple testing burden with a limited number of plausible regulatory SNPs carried forward for disease association testing. This approach was motivated by prior findings that psychiatric and other disease-associated SNPs tag expression quantitative trait loci (eQTL) more often than unassociated SNPs (26-28). Other studies have successfully used cis-eQTL mapping to nominate SNPs and consequently find associations with complex diseases, such as Crohn's disease (29), chronic obstructive pulmonary disease (30), and amyotrophic lateral sclerosis (31). We used cis-eQTL mapping to identify SNPs associated with OPRM1 mRNA expression in human prefrontal cortex from 224 BrainCloud cohort participants who had no evidence of drug use/abuse at the time of death and tested the putative cis-eQTL SNPs for association with heroin addiction across three independent cohorts totaling 16,729 (4,287 cases and 12,442 controls). Our findings revealed replicable and highly significant SNP associations with heroin addiction and provided strong support of OPRM1 as an important susceptibility gene for heroin addiction.
