As an initial step, we conducted an exhaustive SNP discovery survey surrounding the neuronal nAChR coding regions in a small sample selected to represent the most extreme heavy and light dependent smokers. We used a genomic resequencing strategy to generate a dense set of variants in α-like nAChR subunits (α2, α3, α4, α5, α6, α9, and α10) and β-like nAChR subunits (β2, β3, and β4) in 144 smokers and 48 population-matched non-smokers. This survey identified 262 SNPs, including 38 nonsynonymous, 35 synonymous, 57 UTR, 1 stop, and 1 frameshift (see Table S2 for location and allele frequency). The stop and frameshift alleles, both located in CHRNA6, were each observed as heterozygotes in single individuals, indicating that the depth of the resequencing survey reached the boundary of rare loss-of-function alleles. For a preliminary χ2 analysis of association in the resequencing sample, we subdivided the 144 smokers into high (n = 72) and low-dependent (n = 72) categories. Even with this small selected sample set, a nominally significant association signal (P<0.01) was observed for five SNPs located in the CHRNA5-A3-B4 cluster on
