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

被引：480

作者：

McKay, James D. ^{[1
]}

Hung, Rayjean J. ^{[2
]}

Han, Younghun ^{[3
]}

Zong, Xuchen ^{[2
]}

Carreras-Torres, Robert ^{[1
]}

Christiani, David C. ^{[4
,5
]}

Caporaso, Neil E. ^{[6
]}

Johansson, Mattias ^{[1
]}

Xiao, Xiangjun ^{[3
]}

Li, Yafang ^{[3
]}

Byun, Jinyoung ^{[3
]}

Dunning, Alison ^{[7
]}

Pooley, Karen A. ^{[7
]}

Qian, David C. ^{[3
]}

Ji, Xuemei ^{[3
]}

Liu, Geoffrey ^{[2
]}

Timofeeva, Maria N. ^{[1
]}

Bojesen, Stig E. ^{[8
,9
,10
]}

Wu, Xifeng ^{[11
]}

Le Marchand, Loic ^{[12
]}

Albanes, Demetrios ^{[6
]}

Bickeboeller, Heike ^{[13
]}

Aldrich, Melinda C. ^{[14
]}

Bush, William S. ^{[15
]}

Tardon, Adonina ^{[16
,17
]}

Rennert, Gad ^{[18
,19
]}

Teare, M. Dawn ^{[20
]}

Field, John K. ^{[21
]}

Kiemeney, Lambertus A. ^{[22
,23
]}

Lazarus, Philip ^{[24
]}

Haugen, Aage ^{[4
,25
]}

Lam, Stephen ^{[26
]}

Schabath, Matthew B. ^{[27
]}

Andrew, Angeline S. ^{[28
]}

Shen, Hongbing ^{[29
]}

Hong, Yun-Chul ^{[30
]}

Yuan, Jian-Min ^{[31
]}

Bertazzi, Pier Alberto ^{[32
,33
]}

Pesatori, Angela C. ^{[33
]}

Ye, Yuanqing ^{[11
]}

Diao, Nancy ^{[4
,5
]}

Su, Li ^{[4
,5
]}

Zhang, Ruyang ^{[4
,5
]}

Brhane, Yonathan ^{[2
]}

Leighl, Natasha ^{[34
]}

Johansen, Jakob S. ^{[35
]}

Mellemgaard, Anders ^{[35
]}

Saliba, Walid ^{[18
,19
]}

Haiman, Christopher A. ^{[36
]}

Wilkens, Lynne R. ^{[12
]}

机构：

[1] WHO, Int Agcy Res Canc, Lyon, France

[2] Univ Toronto, Sinai Hlth Syst, Lunenfeld Tanenbaum Res Inst, Toronto, ON, Canada

[3] Geisel Sch Med Dartmouth, Biomed Data Sci, Hanover, NH USA

[4] Harvard TH Chan Sch Publ Hlth, Dept Environm Hlth, Boston, MA USA

[5] Harvard Med Sch, Massachusetts Gen Hospital, Boston, MA USA

[6] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA

[7] Univ Cambridge, Ctr Canc Genet Epidemiol, Cambridge, England

[8] Copenhagen Univ Hosp, Herlev & Gentofte Hosp, Dept Clin Biochem, Copenhagen, Denmark

[9] Univ Copenhagen, Fac Hlth & Med Sci, Copenhagen, Denmark

[10] Herlev & Gentofte Hosp, Copenhagen Gen Populat Study, Copenhagen, Denmark

[11] Univ Texas MD Anderson Canc Ctr, Dept Epidemiol, Houston, TX 77030 USA

[12] Univ Hawaii, Canc Ctr, Epidemiol Program, Honolulu, HI 96822 USA

[13] Georg August Univ Gottingen, Univ Med Ctr, Dept Genet Epidemiol, Gottingen, Germany

[14] Vanderbilt Univ, Med Ctr, Div Epidemiol, Dept Thorac Surg, Nashville, TN USA

[15] Case Western Reserve Univ, Sch Med, Dept Epidemiol & Biostat, Cleveland, OH 44106 USA

[16] Univ Oviedo, Oviedo, Spain

[17] CIBERESP, Fac Med, Oviedo, Spain

[18] Clalit Natl Canc Control Ctr, Carmel Med Ctr, Haifa, Israel

[19] Techn Fac Med, Haifa, Israel

[20] Univ Sheffield, Sch Hlth & Related Res, Sheffield, S Yorkshire, England

[21] Univ Liverpool, Inst Translat Med, Liverpool, Merseyside, England

[22] Radboud Univ Nijmegen, Med Ctr, Dept Hlth Evidence, Nijmegen, Netherlands

[23] Radboud Univ Nijmegen, Med Ctr, Dept Urol, Nijmegen, Netherlands

[24] Washington State Univ, Coll Pharm, Dept Pharmaceut Sci, Spokane, WA USA

[25] Nat Inst Occupat Hlth, Oslo, Norway

[26] British Columbia Canc Agcy, Vancouver, BC, Canada

[27] H Lee Moffitt Canc Ctr & Res Inst, Dept Canc Epidemiol, Tampa, FL USA

[28] Geisel Sch Med, Dept Epidemiol, Hanover, NH USA

[29] Nanjing Med Univ, Sch Publ Hlth, Dept Epidemiol & Biostat,Collaborat Innovat Ctr C, Jiangsu Key Lab Canc Biomarkers Prevent & Treatme, Nanjing, Jiangsu, Peoples R China

[30] Seoul Natl Univ, Coll Med, Dept Prevent Med, Seoul, South Korea

[31] Univ Pittsburgh, Canc Inst, Pittsburgh, PA USA

[32] IRCCS Fdn Ca Granda Osped Maggiore Policlin, Dept Prevent Med, Milan, Italy

[33] Univ Milan, Dept Clin Sci & Community Health DISCCO, Milan, Italy

[34] Univ Hlth Network, Princess Margaret Canc Ctr, Toronto, ON, Canada

[35] Copenhagen Univ Hosp, Herlev & Gentofte Hosp, Dept Oncol, Copenhagen, Denmark

[36] Univ Southern Calif, Norris Comprehens Canc Ctr, Keck Sch Med, Dept Prevent Med, Los Angeles, CA USA

[37] Sejong Univ, Dep Integrat Biosci & Biotechnol, Seoul, South Korea

[38] Lund Univ, Dept Pathol, Lund, Sweden

[39] Lund Univ, Fac Med, Lund, Sweden

[40] Imperial Coll London, Sch Publ Hlth, St Marys Campus, London, England

[41] Aarhus Univ, Dept Publ Hlth, Sect Epidemiol, Aarhus, Denmark

[42] Hellen Hlth Fdn, Athens, Greece

[43] Sci Inst Tuscany, CSPO Canc Res & Prevent Ctr, Mol & Nutr Epidemiol Unit, Florence, Italy

[44] Fred Hutchinson Canc Res Ctr, Program Epidemiol, Seattle, WA 98104 USA

[45] Huntsman Canc Inst, Salt Lake City, UT USA

[46] Univ Utah, Huntsman Canc Inst, Dept Populat Hlth Sci, Salt Lake City, UT USA

[47] Swedish Med Grp, Seattle, WA USA

[48] Univ Sheffield, Dept Oncol, Sheffield, S Yorkshire, England

[49] Helmholtz Zentrum Munchen German Res Ctr Environm, Inst Epidemiol 2, Neuherberg, Germany

[50] Ludwig Maximilians Univ Munchen, Inst Med Informat Biometry & Epidemiol, Munich, Germany

来源：

NATURE GENETICS | 2017年 / 49卷 / 07期

基金：

加拿大健康研究院;

关键词：

GENOME-WIDE ASSOCIATION; TELOMERE LENGTH; CROHNS-DISEASE; RISK; VARIANTS; ARCHITECTURE; METAANALYSIS; IMPUTATION; COMPONENT;

D O I：

10.1038/ng.3892

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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 genomewide 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.

引用

页码：1126 / +

页数：9

共 43 条

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← 1 2 3 4 5 →

共 43 条

[1] The OncoArray Consortium: A Network for Understanding the Genetic Architecture of Common Cancers [J].

Amos, Christopher I. ;

Dennis, Joe ;

Wang, Zhaoming ;

Byun, Jinyoung ;

Schumacher, Fredrick R. ;

Gayther, Simon A. ;

Casey, Graham ;

Hunter, David J. ;

Sellers, Thomas A. ;

Gruber, Stephen B. ;

Dunning, Alison M. ;

Michailidou, Kyriaki ;

Fachal, Laura ;

Doheny, Kimberly ;

Spurdle, Amanda B. ;

Li, Yafang ;

Xiao, Xiangjun ;

Romm, Jane ;

Pugh, Elizabeth ;

Coetzee, Gerhard A. ;

Hazelett, Dennis J. ;

Bojesen, Stig E. ;

Caga-Anan, Charlisse ;

Haiman, Christopher A. ;

Kamal, Ahsan ;

Luccarini, Craig ;

Tessier, Daniel ;

Vincent, Daniel ;

Bacot, Francois ;

Van den Berg, David J. ;

Nelson, Stefanie ;

Demetriades, Stephen ;

Goldgar, David E. ;

Couch, Fergus J. ;

Forman, Judith L. ;

Giles, Graham G. ;

Conti, David V. ;

Bickeboeller, Heike ;

Risch, Angela ;

Waldenberger, Melanie ;

Brueske-Hohlfeld, Irene ;

Hicks, Belynda D. ;

Ling, Hua ;

McGuffog, Lesley ;

Lee, Andrew ;

Kuchenbaecker, Karoline ;

Soucy, Penny ;

Manz, Judith ;

Cunningham, Julie M. ;

Butterbach, Katja .

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Gudbjartsson, DF ;

Sulem, P ;

Kristjansson, K ;

Arnason, S ;

Gulcher, JR ;

Bjornsson, J ;

Kong, A ;

Thorsteinsdottir, U ;

Stefansson, K .

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DeLuca, David S. ;

Segre, Ayellet V. ;

Sullivan, Timothy J. ;

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Gelfand, Ellen T. ;

Trowbridge, Casandra A. ;

Maller, Julian B. ;

Tukiainen, Taru ;

Lek, Monkol ;

Ward, Lucas D. ;

Kheradpour, Pouya ;

Iriarte, Benjamin ;

Meng, Yan ;

Palmer, Cameron D. ;

Esko, Tonu ;

Winckler, Wendy ;

Hirschhorn, Joel N. ;

Kellis, Manolis ;

MacArthur, Daniel G. ;

Getz, Gad ;

Shabalin, Andrey A. ;

Li, Gen ;

Zhou, Yi-Hui ;

Nobel, Andrew B. ;

Rusyn, Ivan ;

Wright, Fred A. ;

Lappalainen, Tuuli ;

Ferreira, Pedro G. ;

Ongen, Halit ;

Rivas, Manuel A. ;

Battle, Alexis ;

Mostafavi, Sara ;

Monlong, Jean ;

Sammeth, Michael ;

Mele, Marta ;

Reverter, Ferran ;

Goldmann, Jakob M. ;

Koller, Daphne ;

Guigo, Roderic ;

McCarthy, Mark I. ;

Dermitzakis, Emmanouil T. ;

Gamazon, Eric R. ;

Im, Hae Kyung ;

Konkashbaev, Anuar ;

Nicolae, Dan L. ;

Cox, Nancy J. ;

Flutre, Timothee ;

Wen, Xiaoquan ;

Stephens, Matthew .

SCIENCE, 2015, 348 (6235) :648-660

[4] Sixteen new lung function signals identified through 1000 Genomes Project reference panel imputation [J].

Artigas, Maria Soler ;

Wain, Louise V. ;

Miller, Suzanne ;

Kheirallah, Abdul Kader ;

Huffman, Jennifer E. ;

Ntalla, Ioanna ;

Shrine, Nick ;

Obeidat, Ma'en ;

Trochet, Holly ;

McArdle, Wendy L. ;

Alves, Alexessander Couto ;

Hui, Jennie ;

Zhao, Jing Hua ;

Joshi, Peter K. ;

Teumer, Alexander ;

Albrecht, Eva ;

Imboden, Medea ;

Rawal, Rajesh ;

Lopez, Lorna M. ;

Marten, Jonathan ;

Enroth, Stefan ;

Surakka, Ida ;

Polasek, Ozren ;

Lyytikainen, Leo-Pekka ;

Granell, Raquel ;

Hysi, Pirro G. ;

Flexeder, Claudia ;

Mahajan, Anubha ;

Beilby, John ;

Bosse, Yohan ;

Brandsma, Corry-Anke ;

Campbell, Harry ;

Gieger, Christian ;

Glaeser, Sven ;

Gonzalez, Juan R. ;

Grallert, Harald ;

Hammond, Chris J. ;

Harris, Sarah E. ;

Hartikainen, Anna-Liisa ;

Heliovaara, Markku ;

Henderson, John ;

Hocking, Lynne ;

Horikoshi, Momoko ;

Hutri-Kahonen, Nina ;

Ingelsson, Erik ;

Johansson, Asa ;

Kemp, John P. ;

Kolcic, Ivana ;

Kumar, Ashish ;

Lind, Lars .

NATURE COMMUNICATIONS, 2015, 6

[5] iCOGS collection provides a collaborative model FOREWORD [J].

Bahcall, Orli G. .

NATURE GENETICS, 2013, 45 (04) :343-343

[6] Genome-wide association defines more than 30 distinct susceptibility loci for Crohn's disease [J].

Barrett, Jeffrey C. ;

Hansoul, Sarah ;

Nicolae, Dan L. ;

Cho, Judy H. ;

Duerr, Richard H. ;

Rioux, John D. ;

Brant, Steven R. ;

Silverberg, Mark S. ;

Taylor, Kent D. ;

Barmada, M. Michael ;

Bitton, Alain ;

Dassopoulos, Themistocles ;

Datta, Lisa Wu ;

Green, Todd ;

Griffiths, Anne M. ;

Kistner, Emily O. ;

Murtha, Michael T. ;

Regueiro, Miguel D. ;

Rotter, Jerome I. ;

Schumm, L. Philip ;

Steinhart, A. Hillary ;

Targan, Stephan R. ;

Xavier, Ramnik J. ;

Libioulle, Cecile ;

Sandor, Cynthia ;

Lathrop, Mark ;

Belaiche, Jacques ;

Dewit, Olivier ;

Gut, Ivo ;

Heath, Simon ;

Laukens, Debby ;

Mni, Myriam ;

Rutgeerts, Paul ;

Van Gossum, Andre ;

Zelenika, Diana ;

Franchimont, Denis ;

Hugot, Jean-Pierre ;

de Vos, Martine ;

Vermeire, Severine ;

Louis, Edouard ;

Cardon, Lon R. ;

Anderson, Carl A. ;

Drummond, Hazel ;

Nimmo, Elaine ;

Ahmad, Tariq ;

Prescott, Natalie J. ;

Onnie, Clive M. ;

Fisher, Sheila A. ;

Marchini, Jonathan ;

Ghori, Jilur .

NATURE GENETICS, 2008, 40 (08) :955-962

[7] Hierarchical modeling identifies novel lung cancer susceptibility variants in inflammation pathways among 10,140 cases and 11,012 controls [J].

Brenner, Darren R. ;

Brennan, Paul ;

Boffetta, Paolo ;

Amos, Christopher I. ;

Spitz, Margaret R. ;

Chen, Chu ;

Goodman, Gary ;

Heinrich, Joachim ;

Bickeboeller, Heike ;

Rosenberger, Albert ;

Risch, Angela ;

Muley, Thomas ;

McLaughlin, John R. ;

Benhamou, Simone ;

Bouchardy, Christine ;

Lewinger, Juan Pablo ;

Witte, John S. ;

Chen, Gary ;

Bull, Shelley ;

Hung, Rayjean J. .

HUMAN GENETICS, 2013, 132 (05) :579-589

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Bulik-Sullivan, Brendan ;

Finucane, Hilary K. ;

Anttila, Verneri ;

Gusev, Alexander ;

Day, Felix R. ;

Loh, Po-Ru ;

Duncan, Laramie ;

Perry, John R. B. ;

Patterson, Nick ;

Robinson, Elise B. ;

Daly, Mark J. ;

Price, Alkes L. ;

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