Rs16969968 and rs578776 in the CHRN A5-A3-B4 gene cluster have statistically independent associations with nicotine dependence. However, these SNPs are not biologically independent [23]: the minor risk allele for rs16969968 (A) occurs on the background of the major allele for rs578776 (C), and not all possible joint genotypes are observed (see Table 3). Because of this pattern of linkage disequilibrium, the joint genotypes at these two loci are equivalent to diplotypes (paired haplotypes). With the minor allele of rs16969968 conferring risk for nicotine dependence and the minor allele of rs578776 (T) being protective (Table 2), analyses of the rs16969968/rs578776 diplotypes indicates significantly increased odds of nicotine dependence associated with the AA/CC diplotype and significantly reduced odds associated with the GG/TT diplotype compared with the GG/CC reference adjusting for age, gender and number of H.S. peers who smoked (Table 3).
