We previously carried out a high-density whole-genome and candidate gene association study of nicotine dependence in a European-descent sample [9, 10]. Among the top association signals were chromosome 15q24-25.1 variants, including a biologically compelling finding at rs16969968, a nonsynonymous SNP in the alpha5 cholinergic nicotinic receptor subunit gene (CHRNA5) [10]. The risk allele at rs16969968 causes an amino acid change (D398N, aspartate to asparagine) in the alpha5 subunit and functional changes in the receptor in vitro [11]. Independent replication of this association with nicotine dependence or smoking has now been confirmed in multiple populations of European descent, using rs16969968 or SNPs highly correlated (r2 ≥ 0.8) with rs16969968 [11–19]. Fine-mapping in our original sample continued to highlight rs16969968 and other highly correlated SNPs, which extend across CHRNA5-CHRNA3-CHRNB4 and into neighboring genes IREB2, PSMA4 and LOC123688 [20].
