In the first genome-wide association study of nicotine dependence [17] and a companion large scale candidate gene study [18] we identified several strong associations with variants in CHRN genes including the single nucleotide polymorphism (SNP) rs16969968 in CHRNA5. Independent studies have replicated the association between nicotine dependence and this specific SNP [19–20] and between nicotine dependence and proxy SNPs that are very highly correlated with rs16969968 (r2 = 0.975) [21–22]. Most recently we completed a dense coverage association study of the complete family of 16 nicotinic receptor subunit genes and nicotine dependence in which 226 SNPs were analyzed [23]. We identified four distinct loci associated with nicotine dependence after multiple test correction: two statistically independent SNPs in the CHRNA5-CHRNA3-CHRNB4 gene cluster (rs16969968 and rs578776), one signal in CHRNB3-CHRNA6 tagged by rs13277254, and a single-SNP association in the CHRND gene (rs12466358).
