With the advent of large genomic data sets, geneticists can examine at a new level the influence of genes on behaviour. Two groups have conducted genome-wide association studies involving lung cancer, and both find that sequences in the nicotinic acetylcholine receptor subunit gene cluster contribute susceptibility, although the groups took different paths to this result. Hung et al. suggest that this susceptibility is not related to smoking status or frequency, and show association with a specific amino acid change. Thorgeirsson et al. find that alleles present in a cluster of nicotinic acid receptor genes do not influence whether or not a person smokes, but do affect the number of cigarettes smoked per day, and are therefore also associated with risk of lung cancer and peripheral arterial disease. Either way, the possible potential of nicotinic acetylcholine receptors as drug targets is underlined. A genome-wide association study for lung cancer finds that genetic sequences in the nicotinic acetylcholine receptor subunit gene cluster contribute susceptibility. Interestingly, this susceptibility is not related to smoking status or frequency, and seems to come from a change in an amino acid in the receptor itself. Lung cancer is the most common cause of cancer death worldwide, with over one million cases annually1. To identify genetic factors that modify disease risk, we conducted a genome-wide association study by analysing 317,139 single-nucleotide polymorphisms in 1,989 lung cancer cases and 2,625 controls from six central European countries. We identified a locus in chromosome region 15q25 that was strongly associated with lung cancer (P = 9 × 10-10). This locus was replicated in five separate lung cancer studies comprising an additional 2,513 lung cancer cases and 4,752 controls (P = 5 × 10-20 overall), and it was found to account for 14% (attributable risk) of lung cancer cases. Statistically similar risks were observed irrespective of smoking status or propensity to smoke tobacco. The association region contains several genes, including three that encode nicotinic acetylcholine receptor subunits (CHRNA5, CHRNA3 and CHRNB4). Such subunits are expressed in neurons and other tissues, in particular alveolar epithelial cells, pulmonary neuroendocrine cells and lung cancer cell lines2,3, and they bind to N′-nitrosonornicotine and potential lung carcinogens4. A non-synonymous variant of CHRNA5 that induces an amino acid substitution (D398N) at a highly conserved site in the second intracellular loop of the protein is among the markers with the strongest disease associations. Our results provide compelling evidence of a locus at 15q25 predisposing to lung cancer, and reinforce interest in nicotinic acetylcholine receptors as potential disease candidates and chemopreventative targets5.

A susceptibility locus for lung cancer maps to nicotinic acetylcholine receptor subunit genes on 15q25