As reported previously, after accounting for the linkage disequilibrium (LD) structure in the region, rs16969968 and rs3743078 (a proxy for rs578776) were identified to be two distinct, significant associations with nicotine dependence. The LD between rs3743078 and rs16969968 was r2 (squared correlation)=0.15 overall with D’=−1.0, due to the LD being in repulsion phase. The prior joint genotype analysis showed the zero cells for certain combination genotypes between the two SNPs (14). For example, the high risk genotype AA at rs16969968 occurs only in combination with the homozygous risk genotype CC at rs3743078. Joint analysis of the uncorrelated SNPs rs3743078 and rs16969968 indicates that these two variants each exert independent influence on nicotine dependence vulnerability. These two variants demonstrate an interesting evolutionary history, with the risk allele for rs16969968 occurring on the background of the higher risk variant for rs3743078. 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. Therefore, in order to verify the above analyses, we conducted our test of interaction logistic regression models for rs16969968 while holding constant the genotype of rs3743078, and vice versa.
