Inclusion of rs877138 as a covariate in the comparison of heroin-dependent cases to neighborhood controls not dependent on illicit drugs yielded suggestive evidence (p<2.5 × 10−3) of a second signal involving rs4492854, an NCAM1 SNP. Further analyses supported a dominant model for liability associated with this SNP’s major allele (OR=1.65; 95%CI 1.26–2.17). An examination of aggregate risk associated with these two SNPs [i.e., the number of rs877138 minor alleles (additive) plus the presence of a copy of the rs4492854 major allele] in data from cases and non-dependent neighborhood controls found that risk varied more than 4-fold on the basis of these two SNPs (Table 4). The proportion of heroin-dependent individuals (shown as the column percentage) was observed to increase with this measure of aggregate risk; the p value for the risk-associated linear trend is 2.74 × 10−9.
