Twin studies have indicated that genes influence individual susceptibility to heavy smoking and other phenotypes related to nicotine dependence (5) although the specific genes have been difficult to identify. However, a recent genome wide association study (GWAS) involving approximately 7,500 people from two European populations found a common haplotype in the CHRNA5-CHRNA3-CHRNB4 gene cluster to be associated with smoking quantity (6). SNPs in these nicotinic receptor subunit genes were also associated with nicotine dependence as defined by the Fagerström Test for Nicotine Dependence (FTND) scores in another GWAS (7) and parallel candidate gene study (8) and with early age of tobacco initiation (9). Recently, three additional GWASs (10, 11, 12) reported that SNPs in the CHRNA5-CHRNA3-CHRNB4 gene cluster are associated with increased risk of lung cancer. One of these studies (10) also found these SNPs to be associated with smoking quantity and nicotine dependence and therefore suggested that the link with lung cancer is primarily mediated through the smoking-related phenotypes. However, the other two studies (11, 12) found little or no evidence for the involvement of smoking behavior in the
