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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.

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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
    •  & Richard S Houlston

    These authors contributed equally to this work.

Affiliations

  1. Department of Epidemiology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, 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
  2. Section of Cancer Genetics, Institute of Cancer Research, SM2 5NG, UK.

    • Peter Broderick
    • , Jayaram Vijayakrishnan
    • , Kate Sullivan
    • , Athena Matakidou
    • , Yufei Wang
    •  & Richard S Houlston
  3. Department of Oncology, University of Cambridge, Cambridge CB2 2RE, UK.

    • Timothy Eisen
  4. Department of Systems Biology, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA.

    • Gordon Mills
  5. Center for Inherited Disease Research, Institute of Genetic Medicine, Johns Hopkins University School of Medicine, 333 Cassell Drive, Suite 2000, Baltimore, Maryland 21224, USA.

    • Kimberly Doheny
    •  & Ya-Yu Tsai

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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 to Christopher I Amos.

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    Supplementary Methods, Supplementary Figure 1, Supplementary Tables 1–7

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DOI

https://doi.org/10.1038/ng.109

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