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.

2nd Faculty of Medicine Charles University Prague Czech Republic

American Cancer Society Atlanta Georgia USA

Behavioral and Urban Health Program Behavioral Health and Criminal Justice Division RTI International Research Triangle Park North Carolina USA

Biomedical Data Science Geisel School of Medicine at Dartmouth Hanover New Hampshire USA

British Columbia Cancer Agency Vancouver British Columbia Canada

Campbell Family Mental Health Research Institute Centre for Addiction and Mental Health Toronto Ontario Canada

Cancer Division QIMR Berghofer Medical Research Institute Brisbane Queensland Australia

Centre for Cancer Genetic Epidemiology University of Cambridge Cambridge UK

Clalit National Cancer Control Center at Carmel Medical Center and Technion Faculty of Medicine Haifa Israel

Clinical Center of Serbia Belgrade Serbia

Copenhagen General Population Study Herlev and Gentofte Hospital Copenhagen Denmark

Department of Biostatistics and Informatics University of Colorado Anschutz Medical Campus Aurora Colorado USA

Department of Cancer Epidemiology H Lee Moffitt Cancer Center and Research Institute Tampa Florida USA

Department of Clinical Biochemistry Herlev and Gentofte Hospital Copenhagen University Hospital Copenhagen Denmark

Department of Clinical Science University of Bergen Bergen Norway

Department of Clinical Sciences and Community Health DISCCO University of Milan Milan Italy

Department of Environmental Health Harvard T H Chan School of Public Health and Massachusetts General Hospital Harvard Medical School Boston Massachusetts USA

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

Department of Epidemiology and Biostatistics School of Medicine Case Western Reserve University Cleveland Ohio USA

Department of Epidemiology and Prevention Russian N N Blokhin Cancer Research Centre Moscow Russian Federation

Department of Epidemiology Geisel School of Medicine Hanover New Hampshire USA

Department of Epidemiology Harvard T H Chan School of Public Health Boston Massachusetts USA

Department of Epidemiology Shanghai Cancer Institute Shanghai China

Department of Epidemiology University of Texas MD Anderson Cancer Center Houston Texas USA

Department of Epidemiology University of Washington Seattle Washington USA

Department of Genetic Epidemiology University Medical Center Georg August University Göttingen Göttingen Germany

Department of Integrative Bioscience and Biotechnology Sejong University Seoul Republic of Korea

Department of Medical Biosciences Umeå University Umeå Sweden

Department of Molecular Medicine Laval University Québec Québec Canada

Department of Oncology Herlev and Gentofte Hospital Copenhagen University Hospital Copenhagen Denmark

Department of Oncology University of Sheffield Sheffield UK

Department of Pathology Lund University Lund Sweden

Department of Pharmaceutical Sciences College of Pharmacy Washington State University Spokane Washington USA

Department of Preventive Medicine IRCCS Foundation Cà Granda Ospedale Maggiore Policlinico Milan Italy

Department of Preventive Medicine Keck School of Medicine University of Southern California Norris Comprehensive Cancer Center Los Angeles California USA

Department of Preventive Medicine Seoul National University College of Medicine Seoul Republic of Korea

Department of Psychiatry Washington University School of Medicine St Louis Missouri USA

Department of Radiation Sciences Umeå University Umeå Sweden

Department of Surgery National Tuberculosis and Lung Diseases Research Institute Warsaw Poland

Department of Thoracic Oncology H Lee Moffitt Cancer Center and Research Institute Tampa Florida USA

Department of Thoracic Surgery Division of Epidemiology Vanderbilt University Medical Center Nashville Tennessee USA

Departments of Health Evidence and Urology Radboud University Medical Center Nijmegen the Netherlands

Departments of Pharmacology and Toxicology and Psychiatry University of Toronto Toronto Ontario Canada

Division of Cancer Epidemiology and Genetics National Cancer Institute US National Institutes of Health Bethesda Maryland USA

Duke National University of Singapore Medical School Singapore

Duncan Cancer Center Baylor College of Medicine Houston Texas USA

eCODE Genetics Amgen Inc Reykjavik Iceland

Epidemiology Program University of Hawaii Cancer Center Honolulu Hawaii USA

Faculty of Health and Medical Sciences University of Copenhagen Copenhagen Denmark

Faculty of Medicine Lund University Lund Sweden

Faculty of Medicine University of Ostrava Ostrava Czech Republic

Fellow Program and Behavioral Health and Criminal Justice Division RTI International Research Triangle Park North Carolina USA

Genetic Epidemiology Group Department of Health Sciences University of Leicester Leicester UK

German Center for Lung Research Heidelberg Germany

Hellenic Health Foundation Athens Greece

Huntsman Cancer Institute Department of Population Health Sciences University of Utah Salt Lake City Utah USA

Huntsman Cancer Institute Salt Lake City Utah USA

Institut Universitaire de Cardiologie et de Pneumologie de Québec Québec Québec Canada

Institute of Epidemiology 2 Helmholtz Zentrum München German Research Center for Environmental Health Neuherberg Germany

Institute of Medical Informatics Biometry and Epidemiology Ludwig Maximilians University Munich Germany

Institute of Medical Statistics and Epidemiology Technical University of Munich Munich Germany

Institute of Pneumology 'Marius Nasta' Bucharest Romania

Institute of Translational Medicine University of Liverpool Liverpool UK

International Agency for Research on Cancer World Health Organization Lyon France

International Organization for Cancer Prevention and Research Belgrade Serbia

Lunenfeld Tanenbaum Research Institute Sinai Health System University of Toronto Toronto Ontario Canada

M Sklodowska Curie Cancer Center Institute of Oncology Warsaw Poland

Markey Cancer Center University of Kentucky Lexington Kentucky USA

Merck Research Laboratories Genetics and Pharmacogenomics Boston Massachusetts USA

Molecular and Nutritional Epidemiology Unit CSPO Scientific Institute of Tuscany Florence Italy

National Institute for Health Research Leicester Respiratory Biomedical Research Unit Glenfield Hospital Leicester UK

National Institute of Occupational Health Oslo Norway

Nofer Institute of Occupational Medicine Department of Environmental Epidemiology Lodz Poland

Program in Epidemiology Fred Hutchinson Cancer Research Center Seattle Washington USA

Public Health Ontario Toronto Ontario Canada

Research Computing Division RTI International Research Triangle Park North Carolina USA

Research Unit of Molecular Epidemiology Helmholtz Zentrum München German Research Center for Environmental Health Neuherberg Germany

School of Health and Related Research University of Sheffield Sheffield UK

School of Medicine University of Belgrade Belgrade Serbia

School of Public Health St Mary's Campus Imperial College London London UK

Section for Epidemiology Department of Public Health Aarhus University Aarhus Denmark

Swedish Medical Group Seattle Washington USA

The Institute of Cancer Research London UK

Thoraxklinik at University Hospital Heidelberg Heidelberg Germany

Translational Lung Research Center Heidelberg Heidelberg Germany

Unit of Nutrition and Cancer Catalan Institute of Oncology Barcelona Spain

University Health Network Princess Margaret Cancer Centre Toronto Ontario Canada

University of British Columbia Centre for Heart Lung Innovation St Paul's Hospital Vancouver British Columbia Canada

University of Groningen University Medical Center Groningen Department of Pathology and Medical Biology GRIAC Research Institute Groningen the Netherlands

University of Oviedo and CIBERESP Faculty of Medicine Oviedo Spain

University of Pittsburgh Cancer Institute Pittsburgh Pennsylvania USA

University of Salzburg and Cancer Cluster Salzburg Salzburg Austria

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