Many aspects of cigarette smoking behavior, including onset of smoking, smoking persistence, and nicotine dependence, cluster in families [4]. In addition to environmental factors (such as peer pressure), evidence from twin studies indicates that genetic factors contribute to the development of smoking and related addictive behaviors with heritability estimates ranging from 60% to 72% [5]–[7]. Genome wide association studies (GWAS) and candidate gene studies of nicotine dependence have identified several variants in the gene cluster encoding the α5, α3, and β4 nicotinic receptor subunits on chromosome 15 that alter risk for nicotine dependence, including an amino acid substitution (aspartic acid to asparagine at codon 398) in the α5 nicotinic receptor subunit gene (CHRNA5) and several non-coding variants [8]–[15]. GWAS using several lung cancer populations have also demonstrated association between lung cancer susceptibility and the same or highly correlated variants in the CHRNA5-CHRNA3-CHRNB4 gene cluster [16]–[18].
