The association signal that we identified is far enough upstream from the OPRM1 coding region – about 300 kb for the lead SNP – to have entirely escaped interrogation in the many previous OPRM1 candidate gene studies.12 The identified locus is non-coding, as is often seen in GWASs, and its molecular function remains unknown. Mechanistic studies in genetically engineered neural cultures might shed light on how the μ-opioid receptor’s response to exogenous opioids differs by genotype.54 We cannot rule out the possibility that, although OPRM1 is the closest gene, the association is partially, or even entirely, attributable to cis- or trans-effects on the expression or function of proteins encoded elsewhere in the genome.
