Second, this project interrogated only the non-synonymous variant rs1799971. As with any statistical association, our finding may reflect a proxy association for which the true functional variant(s) remain to be recognized. Other OPRM1 variants have been associated with addiction and merit consideration for future study (Clarke et al. 2013; Hancock et al. 2015; Zhang et al. 2006a). Analyses of multiple SNPs and haplotypes will also be of future interest: recent evidence indicates an important role in heroin addiction for the haplotype structure of OPRM1, with the A allele of rs1799971 showing association only in the presence of the C allele of rs3778150 (Hancock et al. 2015). Importantly, (Hancock et al. 2015) also found that the G allele of rs1799971 is protective (A allele confers risk) on that background, agreeing with the direction of effect observed in our meta-analysis of general substance dependence.
