Three whole-genome association studies (GWAS) recently identified a region of strong linkage disequilibrium on the long arm of chromosome 15 as being a susceptibility locus for lung cancer. The most likely candidate genes in this region are those that encode subunits of nicotinic acetylcholine receptor A (CHRNA3 and CHRNA5). The conclusions from the three studies differed on whether the link to lung cancer is direct or mediated through differences in smoking behavior. Previous reports had strongly associated these two genes with self-assessed nicotine dependence (1,2). The GWAS by Thorgeirsson et al. (3) confirmed these results by agnostically associating SNPs at 15q24/15q25.1 with self-reported number of cigarettes smoked per day and a nicotine-dependence scale. The other two GWAS by Amos et al. (4) and Hung et al. (5) also considered the lifetime smoking history of their cases and controls but found little evidence that this locus influences smoking behavior. Thus, these authors concluded that the association was primarily with lung cancer. Because the association of smoking with this disease is very strong, it is difficult to detect any residual independent association
