The GWS CNIH3 SNPs are intronic and not highly conserved. Although the observed associations may be due to high LD with a non-genotyped variant, no exonic SNPs in high LD were identified. Epigenetically-mediated changes in gene expression, which have been reported to occur with opioid use,39 are plausible mechanisms for functional associations involving intronic SNPs. Rs10799590 is located within an enhancer that is specific to fetal brain (Figure 1). It is within an H3K4me1peak in fetal brain that DNaseI hypersensitivity data indicate is in an open chromatin state.40–42 It is predicted that rs10799590 is within the binding site of transcription factor (TF) TAL1 (which plays important roles in middle brain GABAergic neuron differentiation68); the G allele has significantly higher binding potential than the A allele (Supplementary Table 6).
