In parallel with these GWAS, several studies using a candidate gene approach have also reported the association of SNPs in the CHRNA5-CHRNA3-CHRNB4 gene cluster with nicotine dependence and smoking quantity (17, 113, 140). Furthermore, a fine mapping study (113) observed that the nonsynonymous SNP rs16969968 in exon 5 of CHRNA5 has consistent effects on the risk for nicotine dependence in both European (odds ratio of 1.40; 95% confidence interval, 1.23–1.59) and African (odds ratio of 2.04; 95% confidence interval, 1.15–3.62) populations, despite a large difference in allele frequency for the SNP. A second locus tagged by rs578776 in the 3′ untranslated region of CHRNA3 that has low linkage disequilibrium with rs16969968 is associated with nicotine dependence in European Americans but not in African Americans. Another linkage disequilibrium bin tagged by an intronic SNP in CHRNA5, rs588765, confers a protective effect for nicotine dependence in populations of European descent (Figure 3) (113, 139). A comprehensive meta-analysis involving more than 32,000 subjects confirmed the three unique loci in this gene cluster that affect smoking quantity (112). In Asians, a locus tagged by
