each risk allele.12, 16, 19 Although the synonymous SNP rs1051730 (Y188Y) in CHRNA3 showed the strongest association, the nonsynonymous SNP rs16969968 (D398N) in CHRNA5 and rs55853698 in the 5′-UTR of CHRNA5 hold more promise of functional importance. In the European samples, conditional on rs16969968 or rs55853698, residual association was detected at rs588765, tagging high expression of CHRNA5 and rs6495308 within CHRNA3 as showing significant association with CPD unconditionally. Liu et al.12 discovered better model fitting when conditioning on rs55853698 and rs6495308 compared with rs16969968 and rs588765 using the Bayesian information criteria (BIC). Both rs588765 and rs6495308 were reported to be in low linkage disequilibrium (LD) with each other (r2 = 0.21) and both to be in only modest LD with the principal SNPs (maximum r2 = 0.47) in subjects of European ancestry.12 However, in the AA samples, no second association signal was detected in this region after conditioning on rs2036527, suggesting that rs20356527 and correlated SNPs in populations of African ancestry define a single common haplotype.19 At the same time, the finding of importance of this gene cluster has been replicated by candidate gene association studies in persons of Asian ancestry8, 11 and different ND phenotype-cotinine concentrations,9 neural responses,121 smoking
