Identification of susceptibility pathways for the role of chromosome 15q25.1 in modifying lung cancer risk

Xuemei Ji, Yohan Bossé, Maria Teresa Landi, Jiang Gui, Xiangjun Xiao, David Qian, Philippe Joubert, Maxime Lamontagne, Yafang Li, Ivan Gorlov, Mariella Biasi, Younghun Han, Olga Gorlova, Rayjean J. Hung, Xifeng Wu, James McKay, Xuchen Zong, Robert Carreras-Torres, David C. Christiani, Neil Caporaso, Mattias Johansson, Geoffrey Liu, Stig E. Bojesen, Loic Marchand, Demetrios Albanes, Heike Bickeböller, Melinda C. Aldrich, William S. Bush, Adonina Tardon, Gad Rennert, Chu Chen, M. Dawn Teare, John K. Field, Lambertus A. Kiemeney, Philip Lazarus, Aage Haugen, Stephen Lam, Matthew B. Schabath, Angeline S. Andrew, Hongbing Shen, Yun-Chul Hong, Jian-Min Yuan, Pier A. Bertazzi, Angela C. Pesatori, Yuanqing Ye, Nancy Diao, Li Su, Ruyang Zhang, Yonathan Brhane, Natasha Leighl, Jakob S. Johansen, Anders Mellemgaard, Walid Saliba, Christopher Haiman, Lynne Wilkens, Ana Fernandez-Somoano, Guillermo Fernandez-Tardon, Erik H. F. M. Heijden, Jin Hee Kim, Juncheng Dai, Zhibin Hu, Michael P. A. Davies, Michael W. Marcus, Hans Brunnström, Jonas Manjer, Olle Melander, David C. Muller, Kim Overvad, Antonia Trichopoulou, Rosario Tumino, Jennifer Doherty, Gary E. Goodman, Angela Cox, Fiona Taylor, Penella Woll, Irene Brüske, Judith Manz, Thomas Muley, Angela Risch, Albert Rosenberger, Kjell Grankvist, Mikael Johansson, Frances Shepherd, Ming-Sound Tsao, Susanne M. Arnold, Eric B. Haura, Ciprian Bolca, Ivana Holcatova, Vladimir Janout, Milica Kontic, Jolanta Lissowska, Anush Mukeria, Simona Ognjanovic, Tadeusz M. Orlowski, Ghislaine Scelo, Beata Swiatkowska, David Zaridze, Per Bakke, Vidar Skaug, Shanbeh Zienolddiny, Eric J. Duell, Lesley M. Butler, Woon-Puay Koh, Yu-Tang Gao, Richard Houlston, John McLaughlin, Victoria Stevens, David C. Nickle, Ma’en Obeidat, Wim Timens, Bin Zhu, Lei Song, María Soler Artigas, Martin D. Tobin, Louise V. Wain, Fangyi Gu, Jinyoung Byun, Ahsan Kamal, Dakai Zhu, Rachel F. Tyndale, Wei-Qi Wei, Stephen Chanock, Paul Brennan and Christopher I. Amos ()
Additional contact information
Xuemei Ji: Geisel School of Medicine at Dartmouth
Yohan Bossé: Laval University
Maria Teresa Landi: National Institutes of Health
Jiang Gui: Geisel School of Medicine at Dartmouth
Xiangjun Xiao: Geisel School of Medicine at Dartmouth
David Qian: Geisel School of Medicine at Dartmouth
Philippe Joubert: Institut universitaire de cardiologie et de pneumologie de Québec
Maxime Lamontagne: Institut universitaire de cardiologie et de pneumologie de Québec
Yafang Li: Geisel School of Medicine at Dartmouth
Ivan Gorlov: Geisel School of Medicine at Dartmouth
Mariella Biasi: University of Pennsylvania
Younghun Han: Geisel School of Medicine at Dartmouth
Olga Gorlova: Geisel School of Medicine at Dartmouth
Rayjean J. Hung: Sinai Health System and University of Toronto
Xifeng Wu: The University of Texas MD Anderson Cancer Center
James McKay: World Health Organization
Xuchen Zong: Sinai Health System and University of Toronto
Robert Carreras-Torres: World Health Organization
David C. Christiani: Harvard School of Public Health
Neil Caporaso: National Institutes of Health
Mattias Johansson: World Health Organization
Geoffrey Liu: Sinai Health System and University of Toronto
Stig E. Bojesen: Copenhagen University Hospital
Loic Marchand: University of Hawaii Cancer Center
Demetrios Albanes: National Institutes of Health
Heike Bickeböller: Georg-August-University Göttingen
Melinda C. Aldrich: Vanderbilt University Medical Center
William S. Bush: Vanderbilt University Medical Center
Adonina Tardon: University of Oviedo
Gad Rennert: Carmel Medical Center
Chu Chen: Fred Hutchinson Cancer Research Center
M. Dawn Teare: University of Sheffield
John K. Field: University of Liverpool
Lambertus A. Kiemeney: Radboud Institute for Health Sciences
Philip Lazarus: Washington State University
Aage Haugen: National Institute of Occupational Health
Stephen Lam: British Columbia Cancer Agency
Matthew B. Schabath: H. Lee Moffitt Cancer Center and Research Institute
Angeline S. Andrew: Geisel School of Medicine
Hongbing Shen: Nanjing Medical University
Yun-Chul Hong: Seoul National University College of Medicine
Jian-Min Yuan: University of Pittsburgh Cancer Institute
Pier A. Bertazzi: IRCCS Foundation Ca’Granda Ospedale Maggiore Policlinico
Angela C. Pesatori: IRCCS Foundation Ca’Granda Ospedale Maggiore Policlinico
Yuanqing Ye: The University of Texas MD Anderson Cancer Center
Nancy Diao: Harvard School of Public Health
Li Su: Harvard School of Public Health
Ruyang Zhang: Harvard School of Public Health
Yonathan Brhane: Sinai Health System and University of Toronto
Natasha Leighl: University Health Network—The Princess Margaret Cancer Centre
Jakob S. Johansen: Copenhagen University Hospital
Anders Mellemgaard: Copenhagen University Hospital
Walid Saliba: Carmel Medical Center
Christopher Haiman: University of Southern California Norris Comprehensive Cancer Center
Lynne Wilkens: University of Hawaii Cancer Center
Ana Fernandez-Somoano: University of Oviedo
Guillermo Fernandez-Tardon: University of Oviedo
Erik H. F. M. Heijden: Radboud Institute for Health Sciences
Jin Hee Kim: Sejong University
Juncheng Dai: Nanjing Medical University
Zhibin Hu: Nanjing Medical University
Michael P. A. Davies: University of Liverpool
Michael W. Marcus: University of Liverpool
Hans Brunnström: Lund University
Jonas Manjer: Lund University
Olle Melander: Lund University
David C. Muller: Imperial College London
Kim Overvad: Lund University
Antonia Trichopoulou: Hellenic Health Foundation
Rosario Tumino: “Civic-M.P. Arezzo” Hospital, ASP
Jennifer Doherty: Geisel School of Medicine
Gary E. Goodman: Fred Hutchinson Cancer Research Center
Angela Cox: University of Sheffield
Fiona Taylor: University of Sheffield
Penella Woll: University of Sheffield
Irene Brüske: German Research Center for Environmental Health
Judith Manz: German Research Center for Environmental Health
Thomas Muley: Thoraxklinik at University Hospital Heidelberg
Angela Risch: University of Salzburg
Albert Rosenberger: Georg-August-University Göttingen
Kjell Grankvist: Umeå University
Mikael Johansson: Umeå University
Frances Shepherd: Princess Margaret Cancer Centre
Ming-Sound Tsao: Princess Margaret Cancer Centre
Susanne M. Arnold: University of Kentucky
Eric B. Haura: H. Lee Moffitt Cancer Center and Research Institute
Ciprian Bolca: Institute of Pneumology “Marius Nasta”
Ivana Holcatova: Charles University
Vladimir Janout: Charles University
Milica Kontic: University of Belgrade
Jolanta Lissowska: M. Sklodowska-Curie Institute—Oncology Center
Anush Mukeria: Russian N.N. Blokhin Cancer Research Centre
Simona Ognjanovic: International Organization for Cancer Prevention and Research
Tadeusz M. Orlowski: National Tuberculosis and Lung Diseases Research Institute
Ghislaine Scelo: World Health Organization
Beata Swiatkowska: Nofer Institute of Occupational Medicine
David Zaridze: Russian N.N. Blokhin Cancer Research Centre
Per Bakke: University of Bergen
Vidar Skaug: National Institute of Occupational Health
Shanbeh Zienolddiny: National Institute of Occupational Health
Eric J. Duell: Catalan Institute of Oncology (ICO-IDIBELL)
Lesley M. Butler: University of Pittsburgh Cancer Institute
Woon-Puay Koh: Duke–NUS Medical School
Yu-Tang Gao: Shanghai Cancer Institute
Richard Houlston: The Institute of Cancer Research
John McLaughlin: Public Health Ontario
Victoria Stevens: American Cancer Society, Inc.
David C. Nickle: Merck Research Laboratories
Ma’en Obeidat: The University of British Columbia
Wim Timens: University Medical Center Groningen
Bin Zhu: National Institutes of Health
Lei Song: National Institutes of Health
María Soler Artigas: University of Leicester
Martin D. Tobin: University of Leicester
Louise V. Wain: University of Leicester
Fangyi Gu: National Institutes of Health
Jinyoung Byun: Geisel School of Medicine at Dartmouth
Ahsan Kamal: Geisel School of Medicine at Dartmouth
Dakai Zhu: Geisel School of Medicine at Dartmouth
Rachel F. Tyndale: University of Toronto
Wei-Qi Wei: Vanderbilt University
Stephen Chanock: National Institutes of Health
Paul Brennan: World Health Organization
Christopher I. Amos: Geisel School of Medicine at Dartmouth

Nature Communications, 2018, vol. 9, issue 1, 1-15

Abstract: Abstract Genome-wide association studies (GWAS) identified the chromosome 15q25.1 locus as a leading susceptibility region for lung cancer. However, the pathogenic pathways, through which susceptibility SNPs within chromosome 15q25.1 affects lung cancer risk, have not been explored. We analyzed three cohorts with GWAS data consisting 42,901 individuals and lung expression quantitative trait loci (eQTL) data on 409 individuals to identify and validate the underlying pathways and to investigate the combined effect of genes from the identified susceptibility pathways. The KEGG neuroactive ligand receptor interaction pathway, two Reactome pathways, and 22 Gene Ontology terms were identified and replicated to be significantly associated with lung cancer risk, with P values less than 0.05 and FDR less than 0.1. Functional annotation of eQTL analysis results showed that the neuroactive ligand receptor interaction pathway and gated channel activity were involved in lung cancer risk. These pathways provide important insights for the etiology of lung cancer.

Date: 2018
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DOI: 10.1038/s41467-018-05074-y

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