Nicotine dependence-associated variants in CHRNA5-CHRNA3-CHRNB444, 72 and CHRNA423, 67 have been previously shown to associate with lung cancer and other smoking-related diseases. Our study shows that the nicotine dependence-associated SNPs in DNMT3B and DBH are also associated with lung cancer (Supplementary Table 7). These findings may reflect the SNPs acting indirectly on lung through their influence on smoking (Supplementary Table 8). Alternatively, because DBH is expressed in the lung73 and DNMT3B overexpression has been shown in lung cancer, we cannot exclude the possibility that either of these SNPs act directly to promote lung cancer through an unknown mechanism.53 The DNMT3B and DBH SNPs were both associated with squamous cell lung carcinoma. This histological subtype has a strong association with smoking and occurs infrequently in never-smokers. In contrast, neither SNP is associated with adenocarcinoma, a subtype that has a weaker association with smoking74 and an increasing prevalence over time among never-smokers.75 Histology-specific associations are not uncommon for lung cancer genetic loci.39
