A more complete understanding of the biological factors that underlie the risk of developing heroin addiction is needed to combat its high prevalence and societal impact. To date, no specific genetic variants have been conclusively identified despite much research focused on OPRM1 and its missense SNP rs1799971. Our hypothesis-generating approach of converging cis-eQTL mapping and SNP-disease association testing led to the identification of minor alleles at two OPRM1 intron 1 SNPs (rs3778150 and rs3823010) that are consistently associated with increased risk of heroin addiction across independent cohorts with P values that even exceed the stringent genome-wide significance threshold (P<5×10−8). Our findings highlight the importance of OPRM1 intron 1 and its underlying haplotype structure that provides an explanation for the widely-studied but largely inconsistent association observed for rs1799971, giving credence to the prior suggestion that haplotypes carrying noncoding regulatory SNPs may explain the rs1799971 inconsistencies (19, 63). Consideration of these intronic SNPs and their regulatory effects on OPRM1 expression in disease-relevant human brain tissues is needed to better understand the role of OPRM1 in influencing risk of heroin and other addictions.
