to the association of variants of this gene cluster with ND. For example, Saccone et al. (2007) first reported significant associations of CHRNA5/A3/B4 cluster variants with ND in a large-scale candidate gene-based case-control study of 1050 cases and 879 controls of European ancestry where cases were defined as individuals with an FTND score of ≥ 4 and controls were individuals who smoked at least 100 cigarettes over a lifetime but had an FTND score of 0. Their results indicated rs16699968 (P = 0.0006), a nonsynonymous coding SNP in exon 5 of CHRNA5, and rs578776 (P = 0.0003) in the 3′-UTR of CHRNA3 showed the strongest associations. In another independent GWAS study, Berrettini et al. (2008) identified two other SNPs in CHRNA3 (rs1317286 and rs6495308) associated with cigarettes per day (CPD; P = 0.000003 and 0.00007, respectively) in three independent European samples, although none of the individual SNPs remained statistically significant after correction for multiple testing at the genome-wide level. Most recently, a candidate gene-based study (Weiss and others 2008) revealed a significant association of the variants in this cluster with degree of ND in participants of European origin who began daily smoking at or before the age of 16, but
