A second variant in the CHRNA5-CHRNA3-CHRNB4 cluster, rs578776, constitutes a distinct, significantly associated locus that also warrants further study. This SNP was previously noted to have a false discovery rate of 0.09 (Saccone et al., 2007a); with our denser coverage it remains the most significant representative of this second locus. Joint analysis of the uncorrelated SNPs rs578776 and rs16969968 indicates that these two variants each exert independent influence on nicotine dependence vulnerability. Though |D’| between these SNPs is 1, the low r2 between them means that the disease association at one does not statistically explain the disease association at the other. These two variants demonstrate an interesting evolutionary history, with the risk allele for rs16969968 occurring on the background of the higher risk variant for rs578776 (Table III). Although not all genotype combinations occur because of this history, the three genotypes at one locus on a fixed background for the other demonstrate a clear pattern of altered risk (Table III, first row and first column). It is unclear from our genetic data whether the functional variants underlying this susceptibility reside within the same CHRN gene or reflect variation in two different genes.
