A candidate-gene association study that examined SNPs in 348 genes identified a cluster of nicotinic receptor subunits (CHRNA3-CHRNA5-CHRNB4) on chromosome 15 as being involved in nicotine dependence (Saccone et al. 2007). Since then, this region has become the most significant and best replicated of any GWAS of substance use disorders. In particular, the number of cigarettes smoked per day shows an especially strong signal at this locus (Thorgeirsson et al. 2008, 2010; Amos et al. 2008a; Liu et al. 2010; Tobacco and Genetics Consortium. 2010), nicotine dependence is also associated with this locus (Thorgeirsson et al. 2008; Saccone et al. 2007). Finally, this locus is also associated with increased risk for lung cancer and peripheral arterial disease (Thorgeirsson et al. 2008; Amos et al. 2008b; Hung et al. 2008; Truong et al. 2010). Because CHRNA3, CHRNA5 and CHRNB4 are members of a single haplotype block, it has been challenging to determine which SNP(s) in which gene(s) cause the association and whether the association is due to coding differences (e.g., rs16969968 which causes D398N substitution in CHRNA5) or expression differences, which
