We next examined the effects of dividing neighborhood controls into subgroups based on their lifetime history of illicit and licit drug dependence (Supplemental Table 1 shows a hierarchical breakdown). We found that the association signal became stronger as the criterion for exclusion of individuals with lifetime drug dependence was more narrowly defined (Supplemental Table 6). In the comparison between heroin-dependent cases and neighborhood controls not dependent on any illicit drugs (Table 2), significant association was found for three SNPs (rs877138, rs4938013, and rs7130431) in high LD (Figure) with rs877138, the most strongly associated SNP [odds ratio [OR] = 1.59; 95%CI, (1.32–1.92); p = 9.7 × 10−7]. In contrast, for the comparison between cases and illicit drug-dependent neighborhood controls, only a single SNP reached even nominal significance. A within-neighborhood control group comparison of individuals with and without a lifetime history of illicit drug dependence found that rs877138 was again the most highly associated SNP (p= 8.0 × 10−4), indicating that liability attributable to this variant likely extends to risk for dependence on other illicit drugs.
