A plausible explanation for this finding is that, among the three receptor genes, OPRM1 variants produce the strongest effect on substance dependence; OPRD1 variants combine with OPRM1 variants to generate an additive (or possibly synergistic) effect; and OPRK1 variants can modulate the effects of OPRM1 or OPRD1 variants. This evidence concerns the gene OPRD1 and substance dependence.