Genome-wide association scan of tag SNPs identifies a susceptibility locus for lung cancer at 15q25.1 (original) (raw)
- Letter
- Published: 02 April 2008
- Xifeng Wu1,
- Peter Broderick2,
- Ivan P Gorlov1,
- Jian Gu1,
- Timothy Eisen3,
- Qiong Dong1,
- Qing Zhang1,
- Xiangjun Gu1,
- Jayaram Vijayakrishnan2,
- Kate Sullivan2,
- Athena Matakidou2,
- Yufei Wang2,
- Gordon Mills4,
- Kimberly Doheny5,
- Ya-Yu Tsai5,
- Wei Vivien Chen1,
- Sanjay Shete1,
- Margaret R Spitz1 na1 &
- …
- Richard S Houlston2 na1
Nature Genetics volume 40, pages 616–622 (2008)Cite this article
- 4417 Accesses
- 993 Citations
- 45 Altmetric
- Metrics details
Abstract
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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on SpringerLink
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Additional access options:
Similar content being viewed by others
References
- 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 - 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).
Article CAS Google Scholar - Jonsson, S. et al. Familial risk of lung carcinoma in the Icelandic population. J. Am. Med. Assn. 22, 2977–2983 (2004).
Article Google Scholar - 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).
Article CAS Google Scholar - 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).
Article CAS Google Scholar - Kleinerman, R.A. et al. Hereditary retinoblastoma and risk of lung cancer. J. Natl. Cancer Inst. 92, 2037–2039 (2000).
Article CAS Google Scholar - 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).
Article CAS Google Scholar - 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).
Article CAS Google Scholar - 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).
Article CAS Google Scholar - 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).
Article CAS Google Scholar - 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).
Article CAS Google Scholar - 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).
Article CAS Google Scholar - 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).
Article CAS Google Scholar - 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).
Article CAS Google Scholar - 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).
Article CAS Google Scholar - 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).
Article CAS Google Scholar - 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).
Article CAS Google Scholar - Balding, D.J. A tutorial on statistical methods for population association studies. Nat. Rev. Genet. 7, 781–791 (2006).
Article CAS Google Scholar - Devlin, B., Roeder, K. & Wasserman, L. Genomic control, a new approach to genetic-based association studies. Theor. Popul. Biol. 60, 155–166 (2001).
Article CAS Google Scholar - Price, A.L. et al. Principal components analysis corrects for stratification in genome-wide association studies. Nat. Genet. 38, 904–909 (2006).
Article CAS Google Scholar - Barrett, J.C., Fry, B., Maller, J. & Daly, M.J. Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21, 263–265 (2005).
Article CAS Google Scholar - de Bakker, P.I. et al. Efficiency and power in genetic association studies. Nat. Genet. 37, 1217–1223 (2005).
Article CAS Google Scholar - 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).
Article CAS Google Scholar
Acknowledgements
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
Author notes
- Margaret R Spitz and Richard S Houlston: These authors contributed equally to this work.
Authors and Affiliations
- Department of Epidemiology, The University of Texas M.D. Anderson Cancer Center, Houston, 77030, Texas, USA
Christopher I Amos, Xifeng Wu, Ivan P Gorlov, Jian Gu, Qiong Dong, Qing Zhang, Xiangjun Gu, Wei Vivien Chen, Sanjay Shete & Margaret R Spitz - Section of Cancer Genetics, Institute of Cancer Research, SM2 5NG, UK
Peter Broderick, Jayaram Vijayakrishnan, Kate Sullivan, Athena Matakidou, Yufei Wang & Richard S Houlston - Department of Oncology, University of Cambridge, Cambridge, CB2 2RE, UK
Timothy Eisen - Department of Systems Biology, University of Texas M.D. Anderson Cancer Center, Houston, 77030, Texas, USA
Gordon Mills - Center for Inherited Disease Research, Institute of Genetic Medicine, Johns Hopkins University School of Medicine, 333 Cassell Drive, Suite 2000, Baltimore, 21224, Maryland, USA
Kimberly Doheny & Ya-Yu Tsai
Authors
- Christopher I Amos
You can also search for this author inPubMed Google Scholar - Xifeng Wu
You can also search for this author inPubMed Google Scholar - Peter Broderick
You can also search for this author inPubMed Google Scholar - Ivan P Gorlov
You can also search for this author inPubMed Google Scholar - Jian Gu
You can also search for this author inPubMed Google Scholar - Timothy Eisen
You can also search for this author inPubMed Google Scholar - Qiong Dong
You can also search for this author inPubMed Google Scholar - Qing Zhang
You can also search for this author inPubMed Google Scholar - Xiangjun Gu
You can also search for this author inPubMed Google Scholar - Jayaram Vijayakrishnan
You can also search for this author inPubMed Google Scholar - Kate Sullivan
You can also search for this author inPubMed Google Scholar - Athena Matakidou
You can also search for this author inPubMed Google Scholar - Yufei Wang
You can also search for this author inPubMed Google Scholar - Gordon Mills
You can also search for this author inPubMed Google Scholar - Kimberly Doheny
You can also search for this author inPubMed Google Scholar - Ya-Yu Tsai
You can also search for this author inPubMed Google Scholar - Wei Vivien Chen
You can also search for this author inPubMed Google Scholar - Sanjay Shete
You can also search for this author inPubMed Google Scholar - Margaret R Spitz
You can also search for this author inPubMed Google Scholar - Richard S Houlston
You can also search for this author inPubMed Google Scholar
Contributions
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 toChristopher I Amos.
Supplementary information
Rights and permissions
About this article
Cite this article
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
- Received: 11 December 2007
- Accepted: 04 February 2008
- Published: 02 April 2008
- Issue Date: May 2008
- DOI: https://doi.org/10.1038/ng.109