The rs3778150 minor allele (C) was associated with both reduced OPRM1 expression and increased risk of heroin addiction, with its associations being strongest with European ancestry. It is common for cis-eQTL and disease risk associations to differ by ancestry, possibly due to unmeasured genetic or environmental modifiers (62). The direction of association between OPRM1 expression and risk of heroin addiction has not been conclusively shown. Nonetheless, our observed patterns for the rs3778150 minor allele are consistent with one prior report noting reduced OPRM1 expression levels in thalamus and secondary somatosensory cortex samples of heroin addicts compared to controls and postulating that down-regulation of OPRM1 may play a role in increasing risk of heroin addiction by disrupting the opioid system of a key compensatory response to heroin (25). More specifically, heroin exposure results in reduced μ receptor function, and in response, the opioid system upregulates OPRM1 expression to make more μ receptors available. It is plausible that genetic polymorphisms attenuating OPRM1 expression could hinder this compensatory mechanism, leading to a greater quantity of heroin being needed to trigger a physiological effect and thus increasing risk of becoming addicted to heroin.
