Letter | Published:

Large-scale association analysis identifies new lung cancer susceptibility loci and heterogeneity in genetic susceptibility across histological subtypes

Nature Genetics volume 49, pages 11261132 (2017) | Download Citation


Although several lung cancer susceptibility loci have been identified, much of the heritability for lung cancer remains unexplained. Here 14,803 cases and 12,262 controls of European descent were genotyped on the OncoArray and combined with existing data for an aggregated genome-wide association study (GWAS) analysis of lung cancer in 29,266 cases and 56,450 controls. We identified 18 susceptibility loci achieving genome-wide significance, including 10 new loci. The new loci highlight the striking heterogeneity in genetic susceptibility across the histological subtypes of lung cancer, with four loci associated with lung cancer overall and six loci associated with lung adenocarcinoma. Gene expression quantitative trait locus (eQTL) analysis in 1,425 normal lung tissue samples highlights RNASET2, SECISBP2L and NRG1 as candidate genes. Other loci include genes such as a cholinergic nicotinic receptor, CHRNA2, and the telomere-related genes OFBC1 and RTEL1. Further exploration of the target genes will continue to provide new insights into the etiology of lung cancer.

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Transdisciplinary Research for Cancer in Lung (TRICL) of the International Lung Cancer Consortium (ILCCO) was supported by grants U19-CA148127 and CA148127S1. ILCCO data harmonization is supported by the Cancer Care Ontario Research Chair of Population Studies to R.J.H. and the Lunenfeld-Tanenbaum Research Institute, Sinai Health System. Additional funding information is provided in the Supplementary Note.

The TRICL-ILCCO OncoArray was supported by in-kind genotyping by the Centre for Inherited Disease Research (26820120008i-0-26800068-1).

IARC acknowledges and thanks V. Gaborieau, M. Foll, L. Fernandez-Cuesta, P. Chopard, T. Delhomme and A. Chabrier for their technical assistance in this project.

The authors would like to thank the staff at the Respiratory Health Network Tissue Bank of the FRQS for their valuable assistance with the lung eQTL data set at Laval University. The lung eQTL study at Laval University was supported by the Fondation de l'Institut Universitaire de Cardiologie et de Pneumologie de Québec, the Respiratory Health Network of the FRQS and the Canadian Institutes of Health Research (MOP-123369). Y. Bossé holds a Canada Research Chair in Genomics of Heart and Lung Diseases.

Author information

Author notes

    • James D McKay
    •  & Rayjean J Hung

    These authors contributed equally to this work.


  1. International Agency for Research on Cancer, World Health Organization, Lyon, France.

    • James D McKay
    • , Robert Carreras-Torres
    • , Mattias Johansson
    • , Maria N Timofeeva
    • , Ghislaine Scelo
    •  & Paul Brennan
  2. Lunenfeld-Tanenbaum Research Institute, Sinai Health System, University of Toronto, Toronto, Ontario, Canada.

    • Rayjean J Hung
    • , Xuchen Zong
    • , Geoffrey Liu
    • , Yonathan Brhane
    •  & Linda Kachuri
  3. Biomedical Data Science, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, USA.

    • Younghun Han
    • , Xiangjun Xiao
    • , Yafang Li
    • , Jinyoung Byun
    • , David C Qian
    • , Xuemei Ji
    • , Ahsan Kamal
    • , Claudio Pikielny
    • , Dakai Zhu
    •  & Christopher I Amos
  4. Department of Environmental Health, Harvard T.H. Chan School of Public Health and Massachusetts General Hospital/ Harvard Medical School, Boston, Massachusetts, USA.

    • David C Christiani
    • , Nancy Diao
    • , Li Su
    •  & Ruyang Zhang
  5. Division of Cancer Epidemiology and Genetics, National Cancer Institute, US National Institutes of Health, Bethesda, Maryland, USA.

    • Neil E Caporaso
    • , Demetrios Albanes
    • , Bin Zhu
    • , Lei Song
    • , Fangyi Gu
    • , Stephen Chanock
    •  & Maria Teresa Landi
  6. Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, UK.

    • Alison Dunning
    •  & Karen A Pooley
  7. Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Copenhagen, Denmark.

    • Stig E Bojesen
  8. Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.

    • Stig E Bojesen
  9. Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen, Denmark.

    • Stig E Bojesen
  10. Department of Epidemiology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

    • Xifeng Wu
    •  & Yuanqing Ye
  11. Epidemiology Program, University of Hawaii Cancer Center, Honolulu, Hawaii, USA.

    • Loic Le Marchand
    •  & Lynne R Wilkens
  12. Department of Genetic Epidemiology, University Medical Center, Georg August University Göttingen, Göttingen, Germany.

    • Heike Bickeböller
    •  & Albert Rosenberger
  13. Department of Thoracic Surgery, Division of Epidemiology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.

    • Melinda C Aldrich
  14. Department of Epidemiology and Biostatistics, School of Medicine, Case Western Reserve University, Cleveland, Ohio, USA.

    • William S Bush
  15. University of Oviedo and CIBERESP, Faculty of Medicine, Oviedo, Spain.

    • Adonina Tardon
    • , Ana Fernandez-Somoano
    •  & Guillermo Fernandez-Tardon
  16. Clalit National Cancer Control Center at Carmel Medical Center and Technion Faculty of Medicine, Haifa, Israel.

    • Gad Rennert
    •  & Walid Saliba
  17. School of Health and Related Research, University of Sheffield, Sheffield, UK.

    • M Dawn Teare
  18. Institute of Translational Medicine, University of Liverpool, Liverpool, UK.

    • John K Field
    • , Michael P A Davies
    •  & Michael W Marcus
  19. Departments of Health Evidence and Urology, Radboud University Medical Center, Nijmegen, the Netherlands.

    • Lambertus A Kiemeney
    •  & Henricus F M van der Heijden
  20. Department of Pharmaceutical Sciences, College of Pharmacy, Washington State University, Spokane, Washington, USA.

    • Philip Lazarus
  21. National Institute of Occupational Health, Oslo, Norway.

    • Aage Haugen
    • , Vidar Skaug
    •  & Shanbeh Zienolddiny
  22. British Columbia Cancer Agency, Vancouver, British Columbia, Canada.

    • Stephen Lam
  23. Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA.

    • Matthew B Schabath
  24. Department of Epidemiology, Geisel School of Medicine, Hanover, New Hampshire, USA.

    • Angeline S Andrew
    •  & Jennifer A Doherty
  25. Department of Epidemiology and Biostatistics, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, School of Public Health, Nanjing Medical University, Nanjing, China.

    • Hongbing Shen
    • , Juncheng Dai
    •  & Zhibin Hu
  26. Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea.

    • Yun-Chul Hong
  27. University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania, USA.

    • Jian-Min Yuan
    •  & Lesley M Butler
  28. Department of Preventive Medicine, IRCCS Foundation Cà Granda Ospedale Maggiore Policlinico, Milan, Italy.

    • Pier Alberto Bertazzi
  29. Department of Clinical Sciences and Community Health–DISCCO, University of Milan, Milan, Italy.

    • Pier Alberto Bertazzi
    •  & Angela C Pesatori
  30. University Health Network, Princess Margaret Cancer Centre, Toronto, Ontario, Canada.

    • Natasha Leighl
    • , Frances A Shepherd
    •  & Ming-Sound Tsao
  31. Department of Oncology, Herlev and Gentofte Hospital, Copenhagen University Hospital, Copenhagen, Denmark.

    • Jakob S Johansen
    •  & Anders Mellemgaard
  32. Department of Preventive Medicine, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, California, USA.

    • Christopher A Haiman
  33. Department of Integrative Bioscience and Biotechnology, Sejong University, Seoul, Republic of Korea.

    • Jin Hee Kim
  34. Department of Pathology, Lund University, Lund, Sweden.

    • Hans Brunnström
  35. Faculty of Medicine, Lund University, Lund, Sweden.

    • Jonas Manjer
    •  & Olle Melander
  36. School of Public Health, St Mary's Campus, Imperial College London, London, UK.

    • David C Muller
  37. Section for Epidemiology, Department of Public Health, Aarhus University, Aarhus, Denmark.

    • Kim Overvad
  38. Hellenic Health Foundation, Athens, Greece.

    • Antonia Trichopoulou
  39. Molecular and Nutritional Epidemiology Unit, CSPO (Cancer Research and Prevention Centre), Scientific Institute of Tuscany, Florence, Italy.

    • Rosario Tumino
  40. Program in Epidemiology, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.

    • Jennifer A Doherty
    • , Matt P Barnett
    •  & Chu Chen
  41. Huntsman Cancer Institute, Salt Lake City, Utah, USA.

    • Jennifer A Doherty
  42. Huntsman Cancer Institute, Department of Population Health Sciences, University of Utah, Salt Lake City, Utah, USA.

    • Jennifer A Doherty
  43. Swedish Medical Group, Seattle, Washington, USA.

    • Gary E Goodman
  44. Department of Oncology, University of Sheffield, Sheffield, UK.

    • Angela Cox
    • , Fiona Taylor
    •  & Penella Woll
  45. Institute of Epidemiology II, Helmholtz Zentrum München–German Research Center for Environmental Health, Neuherberg, Germany.

    • Irene Brüske
    •  & H-Erich Wichmann
  46. Institute of Medical Informatics, Biometry and Epidemiology, Ludwig Maximilians University, Munich, Germany.

    • H-Erich Wichmann
  47. Institute of Medical Statistics and Epidemiology, Technical University of Munich, Munich, Germany.

    • H-Erich Wichmann
  48. Research Unit of Molecular Epidemiology, Helmholtz Zentrum München–German Research Center for Environmental Health, Neuherberg, Germany.

    • Judith Manz
    •  & Angela Risch
  49. Thoraxklinik at University Hospital Heidelberg, Heidelberg, Germany.

    • Thomas R Muley
    •  & Angela Risch
  50. Translational Lung Research Center Heidelberg (TLRC-H), Heidelberg, Germany.

    • Thomas R Muley
    •  & Angela Risch
  51. German Center for Lung Research (DZL), Heidelberg, Germany.

    • Angela Risch
  52. University of Salzburg and Cancer Cluster Salzburg, Salzburg, Austria.

    • Angela Risch
  53. Department of Medical Biosciences, Umeå University, Umeå, Sweden.

    • Kjell Grankvist
  54. Department of Radiation Sciences, Umeå University, Umeå, Sweden.

    • Mikael Johansson
  55. Markey Cancer Center, University of Kentucky, Lexington, Kentucky, USA.

    • Susanne M Arnold
  56. Department of Thoracic Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA.

    • Eric B Haura
  57. Institute of Pneumology 'Marius Nasta', Bucharest, Romania.

    • Ciprian Bolca
  58. 2nd Faculty of Medicine, Charles University, Prague, Czech Republic.

    • Ivana Holcatova
  59. Faculty of Medicine, University of Ostrava, Ostrava, Czech Republic.

    • Vladimir Janout
  60. Clinical Center of Serbia, Belgrade, Serbia.

    • Milica Kontic
  61. School of Medicine, University of Belgrade, Belgrade, Serbia.

    • Milica Kontic
  62. M. Sklodowska-Curie Cancer Center, Institute of Oncology, Warsaw, Poland.

    • Jolanta Lissowska
  63. Department of Epidemiology and Prevention, Russian N.N.Blokhin Cancer Research Centre, Moscow, Russian Federation.

    • Anush Mukeria
    •  & David Zaridze
  64. International Organization for Cancer Prevention and Research, Belgrade, Serbia.

    • Simona Ognjanovic
  65. Department of Surgery, National Tuberculosis and Lung Diseases Research Institute, Warsaw, Poland.

    • Tadeusz M Orlowski
  66. Nofer Institute of Occupational Medicine, Department of Environmental Epidemiology, Lodz, Poland.

    • Beata Swiatkowska
  67. Department of Clinical Science, University of Bergen, Bergen, Norway.

    • Per Bakke
  68. Unit of Nutrition and Cancer, Catalan Institute of Oncology (ICO-IDIBELL), Barcelona, Spain.

    • Eric J Duell
  69. Duke–National University of Singapore Medical School, Singapore.

    • Woon-Puay Koh
  70. Department of Epidemiology, Shanghai Cancer Institute, Shanghai, China.

    • Yu-Tang Gao
  71. The Institute of Cancer Research, London, UK.

    • Richard S Houlston
  72. Public Health Ontario, Toronto, Ontario, Canada.

    • John McLaughlin
  73. American Cancer Society, Atlanta, Georgia, USA.

    • Victoria L Stevens
  74. Institut Universitaire de Cardiologie et de Pneumologie de Québec, Québec, Québec, Canada.

    • Philippe Joubert
    • , Maxime Lamontagne
    •  & Yohan Bossé
  75. Merck Research Laboratories, Genetics and Pharmacogenomics, Boston, Massachusetts, USA.

    • David C Nickle
  76. University of British Columbia Centre for Heart Lung Innovation, St Paul's Hospital, Vancouver, British Columbia, Canada.

    • Ma'en Obeidat
  77. University of Groningen, University Medical Center Groningen, Department of Pathology and Medical Biology, GRIAC Research Institute, Groningen, the Netherlands.

    • Wim Timens
  78. Genetic Epidemiology Group, Department of Health Sciences, University of Leicester, Leicester, UK.

    • María Soler Artigas
    • , Martin D Tobin
    •  & Louise V Wain
  79. National Institute for Health Research (NIHR) Leicester Respiratory Biomedical Research Unit, Glenfield Hospital, Leicester, UK.

    • María Soler Artigas
    • , Martin D Tobin
    •  & Louise V Wain
  80. deCODE Genetics, Amgen, Inc., Reykjavik, Iceland.

    • Thorunn Rafnar
    • , Thorgeir E Thorgeirsson
    • , Gunnar W Reginsson
    •  & Kari Stefansson
  81. Behavioral and Urban Health Program, Behavioral Health and Criminal Justice Division, RTI International, Research Triangle Park, North Carolina, USA.

    • Dana B Hancock
  82. Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri, USA.

    • Laura J Bierut
  83. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas, USA.

    • Margaret R Spitz
  84. Research Computing Division, RTI International, Research Triangle Park, North Carolina, USA.

    • Nathan C Gaddis
  85. Department of Biostatistics and Informatics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.

    • Sharon M Lutz
  86. Fellow Program and Behavioral Health and Criminal Justice Division, RTI International, Research Triangle Park, North Carolina, USA.

    • Eric O Johnson
  87. Department of Epidemiology, University of Washington, Seattle, Washington, USA.

    • Sara Lindströem
  88. Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.

    • Xia Jiang
  89. Departments of Pharmacology and Toxicology & Psychiatry, University of Toronto, Toronto, Ontario, Canada.

    • Rachel F Tyndale
  90. Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.

    • Rachel F Tyndale
  91. Cancer Division, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.

    • Georgia Chenevix-Trench
    •  & Jonathan Beesley
  92. Department of Molecular Medicine, Laval University, Québec, Québec, Canada.

    • Yohan Bossé


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  136. Search for Yohan Bossé in:

  137. Search for Stephen Chanock in:

  138. Search for Paul Brennan in:

  139. Search for Maria Teresa Landi in:

  140. Search for Christopher I Amos in:


Drafting of the manuscript: J.D.M., R.J.H., C.I.A. Project coordination: C.I.A., J.D.M., R.J.H., D.C.C., N.E.C., S.C., P. Brennan, M.T.L. Statistical analysis: C.I.A., J.D.M., R.J.H., Y.H., X.Z., R.C.T., X. Ji, X.X., Y.L., J. Byun, K.A.P., D.C.Q., M.N.T., Y. Brhane, D. Zhu. eQTL analysis of candidate variants: J.D.M., Y. Bossé, R.C.T., M.T.L., B.Z., L. Su, M.T.L., M.L. Genomic annotation of candidate variants: D.C.Q., G.C.T., J. Beesley, R.F.T. Assessment of the impact of candidate variants on nicotine addiction: J.D.M., T.R., T.E.T., G.W.R., K.S., D.B.H., L.J.B., R.J.H., SPIRO, L.K., N.C.G., S.M.L., F.G., E.O.J. Assessment of the impact of candidate variants on telomere length: J.D.M., R.J.H., K.A.P., A.D., L.K. Assessment of the impact of candidate variants on lung function: M.D. Tobin, M.S.A., L.V.W., L.K. Sample collection and development of the epidemiological studies: R.J.H., T.R., T.E.T., G.W.R., D.C.C., N.E.C., M.J., G.L., S.E.B., X.W., L.L.M., D.A., H. Bickeböller, M.C.A., W.S.B., A. Tardon, G.R., M.D.T., J.K.F., L.A.K., P.L., A.H., S. Lam, M.B.S., A.S.A., H.S., Y.C.H., J.M.Y., P.A.B., A.C.P., Y.Y., N.D., L. Su, R.Z., Y. Bossé, N.L., J.S.J., A. Mellemgaard, W.S., C.A.H., L.R.W., A.F.-S., G.F.-T., H.F.M.v.d.H., J.H.K., J.D., Z.H., M.P.A.D., M.W.M., H. Brunnström, J. Manjer, O.M., D.C.M., K.O., A. Trichopoulou, R.T., J.A.D., M.P.B., C.C., G.E.G., A.C., F.T., P.W., I.B., H.-E.W., J. Manz, T.R.M., A. Risch, A. Rosenberger, K.G., M.J., F.A.S., M.-S.T., S.M.A., E.B.H., C.B., I.H., V.J., M.K., J.L., A. Mukeria, S.O., T.M.O., G.S., B.S., D. Zaridze, P. Bakke, V.S., S.Z., E.J.D., L.M.B., W.-P.K., Y.-T.G., R.S.H., J. McLaughlin, V.L.S., P.J., M.L., D.C.N., M.O., W.T., L. Song, M.S.A., M.D. Teare, M.R.S., A.K., C.P., R.J.H., J.D.M., M.T.L. Genetic sharing analysis: R.C.T., S. Lindströem, X. Jiang, J.D.M., R.J.H.

Competing interests

T.R., T.E.T., G.W.R. and K.S. are employees of the biotechnology company deCODE Genetics, a subsidiary of Amgen.

Corresponding author

Correspondence to Christopher I Amos.

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1–8, Supplementary Tables 1, 3–6, 8 and 9, and Supplementary Note.

Excel files

  1. 1.

    Supplementary Table 2

    Results from analysis for SNPs with P <1 × 10–5 for overall lung cancer and subsets defined by histology and smoking status.

  2. 2.

    Supplementary Table 7

    Genomic annotations of loci containing sentinel variants.

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