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Genome-wide association scan of tag SNPs identifies a susceptibility locus for lung cancer at 15q25.1


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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Figure 1
Figure 2: The 15q25.1 locus.
Figure 3: Effects of SNPs according to smoking behavior in current, former and never smokers adjusting for age, sex and packyears of tobacco smoke exposure.


  1. 1

    Tokuhata, G.K. & Lilienfeld, A.M. Familial aggregation of lung cancer in humans. J. Natl. Cancer Inst. 30, 289–312 (1963).

    CAS  PubMed  Google Scholar 

  2. 2

    Amos, C.I., Xu, W. & Spitz, M.R. Is there a genetic basis for lung cancer susceptibility? Recent Results Cancer Res. 151, 3–12 (1999).

    CAS  Article  Google Scholar 

  3. 3

    Jonsson, S. et al. Familial risk of lung carcinoma in the Icelandic population. J. Am. Med. Assn. 22, 2977–2983 (2004).

    Article  Google Scholar 

  4. 4

    Hwang, S.J. et al. Lung cancer risk in germline p53 mutation carriers: association between an inherited cancer predisposition, cigarette smoking, and cancer risk. Hum. Genet. 113, 238–243 (2003).

    CAS  Article  Google Scholar 

  5. 5

    Sanders, B.M., Jay, M., Draper, G.J. & Roberts, E.M. Non-ocular cancer in relatives of retinoblastoma patients. Br. J. Cancer 60, 358–365 (1989).

    CAS  Article  Google Scholar 

  6. 6

    Kleinerman, R.A. et al. Hereditary retinoblastoma and risk of lung cancer. J. Natl. Cancer Inst. 92, 2037–2039 (2000).

    CAS  Article  Google Scholar 

  7. 7

    Takemiya, M., Shiraishi, S., Teramoto, T. & Miki, Y. Bloom's syndrome with porokeratosis of Mibelli and multiple cancers of the skin, lung and colon. Clin. Genet. 31, 35–44 (1987).

    CAS  Article  Google Scholar 

  8. 8

    Yamanaka, A., Hirai, T., Ohtake, Y. & Kitagawa, M. Lung cancer associated with Werner's syndrome: a case report and review of the literature. Jpn. J. Clin. Oncol. 27, 415–418 (1997).

    CAS  Article  Google Scholar 

  9. 9

    Bailey-Wilson, J.E. et al. A major lung cancer susceptibility locus maps to chromosome 6q23-25. Am. J. Hum. Genet. 75, 460–474 (2004).

    CAS  Article  Google Scholar 

  10. 10

    Webb, E.L. et al. Search for low penetrance alleles for colorectal cancer through a scan of 1467 non-synonymous SNPs in 2575 cases and 2707 controls with validation by kin-cohort analysis of 14,704 first-degree relatives. Hum. Mol. Genet. 15, 3263–3271 (2006).

    CAS  Article  Google Scholar 

  11. 11

    Zhang, Q. et al. Nicotine induces hypoxia-inducible factor-1alpha expression in human lung cancer cells via nicotinic acetylcholine receptor-mediated signaling pathways. Clin. Cancer Res. 13, 4686–4694 (2007).

    CAS  Article  Google Scholar 

  12. 12

    Lam, D.C. et al. Expression of nicotinic acetylcholine receptor subunit genes in non-small-cell lung cancer reveals differences between smokers and nonsmokers. Cancer Res. 67, 4638–4647 (2007).

    CAS  Article  Google Scholar 

  13. 13

    Minna, J.D. Nicotine exposure and bronchial epithelial cell nicotinic acetylcholine receptor expression in the pathogenesis of lung cancer. J. Clin. Invest. 111, 31–33 (2003).

    CAS  Article  Google Scholar 

  14. 14

    Trombino, S. et al. Alpha7-nicotinic acetylcholine receptors affect growth regulation of human mesothelioma cells: role of mitogen-activated protein kinase pathway. Cancer Res. 64, 135–145 (2004).

    CAS  Article  Google Scholar 

  15. 15

    Ho, Y.S. et al. Tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) induces cell proliferation in normal human bronchial epithelial cells through NFkappaB activation and cyclin D1 up-regulation. Toxicol. Appl. Pharmacol. 205, 133–148 (2005).

    CAS  Article  Google Scholar 

  16. 16

    Saccone, S.F. et al. Cholinergic nicotinic receptor genes implicated in a nicotine dependence association study targeting 348 candidate genes with 3713 SNPs. Hum. Mol. Genet. 16, 36–49 (2007).

    CAS  Article  Google Scholar 

  17. 17

    Purcell, S. et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am. J. Hum. Genet. 81, 559–575 (2007).

    CAS  Article  Google Scholar 

  18. 18

    Balding, D.J. A tutorial on statistical methods for population association studies. Nat. Rev. Genet. 7, 781–791 (2006).

    CAS  Article  Google Scholar 

  19. 19

    Devlin, B., Roeder, K. & Wasserman, L. Genomic control, a new approach to genetic-based association studies. Theor. Popul. Biol. 60, 155–166 (2001).

    CAS  Article  Google Scholar 

  20. 20

    Price, A.L. et al. Principal components analysis corrects for stratification in genome-wide association studies. Nat. Genet. 38, 904–909 (2006).

    CAS  Article  Google Scholar 

  21. 21

    Barrett, J.C., Fry, B., Maller, J. & Daly, M.J. Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21, 263–265 (2005).

    CAS  Article  Google Scholar 

  22. 22

    de Bakker, P.I. et al. Efficiency and power in genetic association studies. Nat. Genet. 37, 1217–1223 (2005).

    CAS  Article  Google Scholar 

  23. 23

    Skol, A.D., Scott, L.J., Abecasis, G.R. & Boehnke, M. Joint analysis is more efficient than replication-based analysis for two-stage genome-wide association studies. Nat. Genet. 38, 209–213 (2006).

    CAS  Article  Google Scholar 

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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.

Author information




Texas: C.I.A. and M.R.S. conceived of this study. M.R.S. established the Texas lung cancer study. C.I.A. supervised and performed the analyses. G.M. provided oversight in manuscript development and in the conduct of genetic studies. I.P.G., Q.D., Q.Z., W.V.C. and X.G. performed statistical analyses. S.S. developed and implemented statistical procedures for joint analysis. X.W. and J.G. oversaw genotyping for Texas studies. ICR: R.S.H. and T.E. established GELCAPS. R.S.H. supervised laboratory analyses. A.M. oversaw GELCAPS and developed the database. P.B. supervised sample organization, genotyping and sequencing. Y.W. provided database management. K.S. and J.V. performed DNA preparation and sequencing. CIDR: K.D. and Y.-Y.T. were responsible for direction of GWA genotyping and genotype data quality assurance conducted by the Center for Inherited Disease Research. All authors contributed to the final paper, with C.I.A., R.S.H., M.R.S., I.P.G., K.D., S.S. and Y.-Y.T. playing key roles.

Corresponding author

Correspondence to Christopher I Amos.

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Supplementary Methods, Supplementary Figure 1, Supplementary Tables 1–7 (PDF 1109 kb)

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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).

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