To identify risk variants for lung cancer, we conducted a multistage genome-wide association study. In the discovery phase, we analyzed 315,450 tagging SNPs in 1,154 current and former (ever) smoking cases of European ancestry and 1,137 frequency-matched, ever-smoking controls from Houston, Texas. For replication, we evaluated the ten SNPs most significantly associated with lung cancer in an additional 711 cases and 632 controls from Texas and 2,013 cases and 3,062 controls from the UK. Two SNPs, rs1051730 and rs8034191, mapping to a region of strong linkage disequilibrium within 15q25.1 containing PSMA4 and the nicotinic acetylcholine receptor subunit genes CHRNA3 and CHRNA5, were significantly associated with risk in both replication sets. Combined analysis yielded odds ratios of 1.32 (P < 1 × 10−17) for both SNPs. Haplotype analysis was consistent with there being a single risk variant in this region. We conclude that variation in a region of 15q25.1 containing nicotinic acetylcholine receptors genes contributes to lung cancer risk.
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Partial support for this study has been provided by US National Institutes of Health grants R01CA133996, R01CA55769, P50 CA70907 and R01CA121197, the Kleberg Center for Molecular Markers at M.D. Anderson Cancer Center, and by support from the Flight Attendants Medical Research Institute. Genotyping services were provided by the Center for Inherited Disease Research (CIDR). CIDR is fully funded through a federal contract from the National Institutes of Health to The Johns Hopkins University, Contract Number N01-HG-65403. We thank the Kelsey Research Foundation for facilitating control selection in Texas. At the Institute for Cancer Research, work was undertaken with support primarily from Cancer Research UK. We are also grateful to the National Cancer Research Network, HEAL and Sanofi-Aventis. A. Matakidou was the recipient of a clinical research fellowship from the Allan J. Lerner Fund. We are also thankful for the unstinting efforts of the study coordinators and interviewers, including S. Honn, P. Porter, S. Ritter and J. Rogers. We also thank the study participants, who had the most critical role in this research.
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Amos, C., Wu, X., Broderick, P. et al. Genome-wide association scan of tag SNPs identifies a susceptibility locus for lung cancer at 15q25.1. Nat Genet 40, 616–622 (2008). https://doi.org/10.1038/ng.109