The 4 OPRD1 SNPs that we found to be most strongly associated with heroin dependence are all located in the first intron of this gene. Although these SNPs are not located at a branch point and do not alter either a splice enhancer or silencer, there is some evidence supporting potential epigenetically-mediated functionality. rs2236855 has a high level of evolutionary conservation (PhyloP Score=1.14) and is located within a DNase I hypersensitivity site in many, but not all, cell types (Fujita et al. 2011) suggesting it could be a cell type specific regulatory element. Both rs2236857 and rs2298897 are located within interspersed repeats: the former in a long interspersed element and the latter in a long terminal repeat (Fujita et al. 2011). The post-hoc examination of the two-SNP haplotype (rs2236857 and rs581111), prompted by the limited attenuation of association signal for rs581111 (also located in intron 1) in an analysis conditioned on the most strongly associated SNP, found evidence of an association stronger by more than an order of magnitude (uncorrected p=1.41 × 10−5). These results are suggestive of a non-genotyped
