The focus of our study was to identify OPRM1 polymorphisms consistently associated with heroin addiction. To increase the likelihood of detecting such associations, we followed the strategy of mapping cis-eQTLs altering OPRM1 expression in human brain from non-addicted participants, nominating this relatively small number of potentially regulatory polymorphisms, and testing them for association with heroin addiction. Among 16 putative cis-eQTL SNPs, we found that rs3778150 had a highly significant association with heroin addiction across three independent cohorts, even surpassing the standard genome-wide significance P value threshold of 5×10−8. Follow-up haplotype analyses showed that the widely-studied missense SNP rs1799971 was associated with heroin addiction only in the presence of the rs3778150 risk allele, suggesting that rs3778150 and its nearby correlated SNPs may explain the inconsistent associations of rs1799971 observed across numerous studies of heroin/opioid addiction.
