Before the GWAS reports, Saccone et al.13 reported significant association of a 3′-UTR variant (rs578776) in CHRNA3 with dichotomized FTND in smokers in a candidate gene association study examining 348 genes. Then, in the GWAS era, five variants in this region reached genome-wide significance in five GWAS and meta-GWAS,12, 16-19 among which four (rs1051730, rs16969968, rs64952308, and rs55853698) were found to be significant in Europeans, and one (rs2036527) was significantly associated with CPD in AAs. The SNPs rs1051730, rs16969968, and rs55853698 are close-tagging proxies (all pairwise r2 > 0.96), 12 and rs2036527 is correlated with rs1051730.19 All the r2s reported in the main text were extracted from the original studies. Thus, these variants were predicted to either tag or potentially cause the principal risk for high smoking quantity attributable to the 15q25 locus, with approximately one CPD step increase for 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
