We have demonstrated that two distinct variant groups in the CHRNA5-CHRNA3-CHRNB4 gene cluster are strongly associated with heavy smoking. Of the eight SNPs associated with increased risk of heavy smoking, only rs16969968 alters the coding sequence of these genes. This SNP was associated with nicotine dependence in previous GWAS and candidate gene studies (7, 8) and is the most likely candidate for the polymorphism responsible for increased risk of heavy smoking. The eleven SNPs associated with decreased risk of heavy smoking are either intronic or are outside the translated region of the three genes. Thus, it is not clear whether one of these SNPs or a polymorphism in LD with these variants is the functional variant responsible for this association. Our findings with the risk and protective SNP genotype combinations define a gradient of genetic predisposition to smoking intensity. The odds of heavy smoking behavior were twice as high in individuals with the highest risk, as compared with the lowest risk genotype combination.
