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.

1st Faculty of Medicine Charles University Kateřinská 32 Prague 121 08 Praha 2 Czech Republic

American Cancer Society Inc Atlanta 30303 GA USA

Annenberg School of Communication University of Pennsylvania Philadelphia 19104 PA USA

Biomedical Data Science Geisel School of Medicine at Dartmouth Hanover 03750 NH USA

British Columbia Cancer Agency 675 West 10th Avenue Vancouver V5Z1L3 Canada

Campbell Family Mental Health Research Institute Centre for Addiction and Mental Health Toronto M6J 1H4 ON Canada

Cancer Cluster Salzburg University of Salzburg Salzburg 5020 Austria

Cancer Registry and Histopathology Department Civic M P Arezzo Hospital ASP Ragusa 97100 Italy

Centre for Heart Lung Innovation St Paul's Hospital The University of British Columbia Vancouver V6Z 1Y6 BC Canada

Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública Campus del Cristo s n Oviedo 33006 Spain

Clalit National Cancer Control Center Carmel Medical Center Haifa 34361 Israel

Clinical Center of Serbia Clinic for Pulmonology School of Medicine University of Belgrade Belgrade 11000 Serbia

Copenhagen General Population Study Herlev and Gentofte Hospital Ringvej 75 Copenhagen Herlev 2730 Denmark

Department of Biomedical Informatics School of Medicine Vanderbilt University Nashville TN 37235 USA

Department of Cancer Epidemiology and Prevention M Sklodowska Curie Institute Oncology Center Warsaw 02 781 Poland

Department of Cancer Epidemiology H Lee Moffitt Cancer Center and Research Institute Tampa 33612 FL USA

Department of Clinical Biochemistry Herlev and Gentofte Hospital Copenhagen University Hospital Copenhagen Herlev 2730 Denmark

Department of Clinical Science University of Bergen Bergen 5021 Norway

Department of Clinical Sciences and Community Health University of Milan Milan 20133 Italy

Department of Environmental Epidemiology Nofer Institute of Occupational Medicine Lodz 91 348 Poland

Department of Environmental Health Harvard School of Public Health Boston 02115 MA 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 101 Longmian Ave Nanjing 211166 PR China

Department of Epidemiology and Biostatistics School of Medicine Case Western Reserve University Cleveland 44106 OH USA

Department of Epidemiology and Prevention Russian N N Blokhin Cancer Research Centre Moscow 115478 Russian Federation

Department of Epidemiology Geisel School of Medicine 1 Medical Center Drive Hanover 03755 NH USA

Department of Epidemiology Shanghai Cancer Institute Shanghai 2200 China

Department of Epidemiology The University of Texas MD Anderson Cancer Center Houston 77030 TX USA

Department of Genetic Epidemiology University Medical Center Georg August University Göttingen Göttingen 37073 Germany

Department of Genetics and Pharmacogenomics Merck Research Laboratories Boston 02115 5727 MA USA

Department of Integrative Bioscience and Biotechnology Sejong University Gwangjin gu Seoul 05029 Republic of Korea

Department of Medical Biosciences Umeå University Umeå 901 85 Sweden

Department of Medicine Massachusetts General Hospital Boston 02115 MA USA

Department of Molecular Medicine Laval University Québec G1V 4G5 Canada

Department of Oncology and Metabolism University of Sheffield Sheffield S10 2RX UK

Department of Oncology Herlev and Gentofte Hospital Copenhagen University Hospital Copenhagen 2730 Denmark

Department of Pathology and Medical Biology GRIAC University of Groningen University Medical Center Groningen Groningen NL 9713 GZ The Netherlands

Department of Pathology Lund University Lund 222 41 Sweden

Department of Pharmaceutical Sciences College of Pharmacy Washington State University Spokane 99210 1495 WA USA

Department of Pharmacology and Toxicology University of Toronto Toronto M5S 1A8 ON Canada

Department of Preventive Medicine IRCCS Foundation Ca'Granda Ospedale Maggiore Policlinico Milan 20133 Italy

Department of Preventive Medicine Keck School of Medicine University of Southern California Norris Comprehensive Cancer Center Los Angeles 90033 CA USA

Department of Preventive Medicine Seoul National University College of Medicine 1 Gwanak ro Gwanak gu Seoul 151 742 Republic of Korea

Department of Psychiatry University of Toronto Toronto M5T 1R8 ON Canada

Department of Radiation Sciences Umeå University Umeå 901 85 Sweden

Department of Surgery National Tuberculosis and Lung Diseases Research Institute Warsaw PL 01 138 Poland

Department of Thoracic Oncology H Lee Moffitt Cancer Center and Research Institute Tampa 33612 KY USA

Department of Thoracic Surgery Division of Epidemiology Vanderbilt University Medical Center Nashville 37203 TN USA

Division of Cancer Epidemiology and Genetics National Cancer Institute National Institutes of Health Bethesda 20892 MD USA

Duke NUS Medical School Singapore 119077 Singapore

Epidemiology Program University of Hawaii Cancer Center Honolulu 96813 HI USA

Faculty of Health and Medical Sciences University of Copenhagen Copenhagen 2200 København N Denmark

Faculty of Medicine Lund University Lund 22100 Sweden

Faculty of Medicine Technion Haifa 34361 Israel

Faculty of Medicine University of Oviedo Oviedo 33006 Spain

Fred Hutchinson Cancer Research Center Seattle 98109 1024 WA USA

Genetic Epidemiology Group Department of Health Sciences University of Leicester Leicester LE1 7RH UK

Hellenic Health Foundation Athens GR 115 27 Greece

Institut universitaire de cardiologie et de pneumologie de Québec Québec G1V 4G5 Canada

Institute of Pneumology Marius Nasta Bucharest RO 050159 Romania

International Agency for Research on Cancer World Health Organization Lyon 69372 CEDEX 08 France

International Organization for Cancer Prevention and Research Belgrade 11070 Serbia

Leicester Respiratory Biomedical Research Unit National Institute for Health Research Glenfield Hospital Leicester LE3 9QP UK

Lunenfeld Tanenbaum Research Institute Sinai Health System and University of Toronto Toronto M5T 3L9 Canada

Markey Cancer Center University of Kentucky 1st Floor 800 Rose Street Lexington 40508 KY USA

National Institute of Occupational Health 0033 Gydas vei 8 0033 Oslo Norway

Perelman School of Medicine University of Pennsylvania Philadelphia 19104 PA USA

Princess Margaret Cancer Centre Toronto M5G2M9 Canada

Public Health Ontario Windsor Ontario N8W 5K5 Canada

Public Health Sciences Division Fred Hutchinson Cancer Research Center Seattle 98109 WA USA

Radboud University Medical Center Radboud Institute for Health Sciences Nijmegen 6525 EZ The Netherlands

Research Unit of Molecular Epidemiology Institute of Epidemiology 2 Helmholtz Zentrum München German Research Center for Environmental Health Neuherberg D 85764 Germany

Roy Castle Lung Cancer Research Programme Institute of Translational Medicine University of Liverpool Liverpool L69 3BX UK

Saw Swee Hock School of Public Health National University of Singapore Singapore 117549 Singapore

School of Health and Related Research University of Sheffield Sheffield S1 4DA UK

School of Public Health St Mary's Campus Imperial College London London W2 1PG UK

Swedish Medical Group Arnold Pavilion Suite 200 Seattle 98104 WA USA

The Institute for Clinical and Translational Research Baylor College of Medicine Houston 77030 TX USA

The Institute of Cancer Research London SW7 3RP England UK

Thoraxklinik at University Hospital Heidelberg Heidelberg 69126 Germany

Translational Lung Research Center Heidelberg Heidelberg 69120 Germany

Unit of Nutrition and Cancer Catalan Institute of Oncology Barcelona 08908 Spain

University Health Network The Princess Margaret Cancer Centre 600 University Avenue Toronto M5G 2C4 Canada

University of Pittsburgh Cancer Institute Pittsburgh 15232 PA USA

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Rare deleterious germline variants and risk of lung cancer

Protein-altering germline mutations implicate novel genes related to lung cancer development