Genome-wide association studies (GWAS) have identified common pancreatic cancer susceptibility variants at 13 chromosomal loci in individuals of European descent. To identify new susceptibility variants, we performed imputation based on 1000 Genomes (1000G) Project data and association analysis using 5,107 case and 8,845 control subjects from 27 cohort and case-control studies that participated in the PanScan I-III GWAS. This analysis, in combination with a two-staged replication in an additional 6,076 case and 7,555 control subjects from the PANcreatic Disease ReseArch (PANDoRA) and Pancreatic Cancer Case-Control (PanC4) Consortia uncovered 3 new pancreatic cancer risk signals marked by single nucleotide polymorphisms (SNPs) rs2816938 at chromosome 1q32.1 (per allele odds ratio (OR) = 1.20, P = 4.88x10 -15), rs10094872 at 8q24.21 (OR = 1.15, P = 3.22x10 -9) and rs35226131 at 5p15.33 (OR = 0.71, P = 1.70x10 -8). These SNPs represent independent risk variants at previously identified pancreatic cancer risk loci on chr1q32.1 ( NR5A2), chr8q24.21 ( MYC) and chr5p15.33 ( CLPTM1L- TERT) as per analyses conditioned on previously reported susceptibility variants. We assessed expression of candidate genes at the three risk loci in histologically normal ( n = 10) and tumor ( n = 8) derived pancreatic tissue samples and observed a marked reduction of NR5A2 expression (chr1q32.1) in the tumors (fold change -7.6, P = 5.7x10 -8). This finding was validated in a second set of paired ( n = 20) histologically normal and tumor derived pancreatic tissue samples (average fold change for three NR5A2 isoforms -31.3 to -95.7, P = 7.5x10 -4-2.0x10 -3). Our study has identified new susceptibility variants independently conferring pancreatic cancer risk that merit functional follow-up to identify target genes and explain the underlying biology.

ARC NET Centre for Applied Research on Cancer University and Hospital Trust of Verona Verona Italy

Bureau of Epidemiologic Research Academy of Athens Athens Greece

Cancer Epidemiology Centre Cancer Council Victoria Melbourne Victoria Australia

Cancer Epidemiology Program University of Hawaii Cancer Center Honolulu Hawaii USA

Cancer Epidemiology Unit University of Oxford Oxford United Kingdom

Cancer Genomics Research Laboratory National Cancer Institute Division of Cancer Epidemiology and Genetics Leidos Biomedical Research Inc Frederick National Laboratory for Cancer Research Frederick Maryland USA

Centre de Recerca en Epidemiologia Ambiental Spain

Centre for Epidemiology and Biostatistics Melbourne School of Population and Global Health The University of Melbourne Victoria Australia

Channing Division of Network Medicine Department of Medicine Brigham and Women's Hospital and Harvard Medical School Boston Massachusetts USA

CIBER de Epidemiología y Salud Pública Madrid Spain

Dalla Lana School of Public Health University of Toronto Toronto Ontario Canada

Department for Determinants of Chronic Diseases Bilthoven The Netherlands

Department of Basic Medical Sciences Laboratory of Biology Medical School National and Kapodistrian University of Athens Athens Greece

Department of Biology University of Pisa Pisa Italy

Department of Biostatistics Harvard School of Public Health Boston Massachusetts USA

Department of Chronic Disease Epidemiology Yale School of Public Health New Haven Connecticut USA

Department of Computational Biology St Jude Children's Research Hospital Memphis Tennessee USA

Department of Digestive Tract Diseases Medical University of Łodz Łodz Poland

Department of Environmental Medicine New York University School of Medicine New York New York USA

Department of Epidemiology and Biostatistics Memorial Sloan Kettering Cancer Center New York New York USA

Department of Epidemiology and Biostatistics School of Public Health Imperial College London London United Kingdom

Department of Epidemiology and Biostatistics University of California San Francisco San Francisco California USA

Department of Epidemiology and Preventive Medicine Monash University Melbourne Victoria Australia

Department of Epidemiology Harvard School of Public Health Boston Massachusetts USA

Department of Epidemiology the Bloomberg School of Public Health Baltimore Maryland USA

Department of Epidemiology University of Washington Seattle Washington USA

Department of Gastroenterology Lithuanian University of Health Sciences Kaunas Lithuania

Department of Gastrointestinal Medical Oncology University of Texas M D Anderson Cancer Center Houston Texas USA

Department of General Surgery University Hospital Heidelberg Heidelberg Germany

Department of General Visceral and Thoracic Surgery University Hamburg Eppendorf Hamburg Germany

Department of Hematology Medical University of Łodz Łodz Poland

Department of Laboratory Medicine University Hospital of Padova Padua Italy

Department of Medical Oncology Dana Farber Cancer Institute Boston Massachusetts USA

Department of Medicine Brigham and Women's Hospital and Harvard Medical School Boston Massachusetts USA

Department of Medicine Memorial Sloan Kettering Cancer Center New York New York USA

Department of Medicine Sidney Kimmel Cancer Center and Johns Hopkins University Baltimore Maryland USA

Department of Molecular Biology of Cancer Institute of Experimental Medicine Academy of Sciences of the Czech Republic Prague Czech Republic

Department of Nutrition Harvard School of Public Health Boston Massachusetts USA

Department of Obstetrics and Gynecology New York University School of Medicine New York New York USA

Department of Oncology Sidney Kimmel Cancer Center and Johns Hopkins University Baltimore Maryland USA

Department of Oncology the Johns Hopkins University School of Medicine Baltimore Maryland USA

Department of Pathology Sidney Kimmel Cancer Center and Johns Hopkins University Baltimore Maryland USA

Department of Population Health QIMR Berghofer Medical Research Institute Brisbane Queensland Australia

Department of Social and Preventive Medicine Faculty of Medicine University of Malaya Kuala Lumpur Malaysia

Department of Social and Preventive Medicine University at Buffalo Buffalo New York USA

Department of Surgery Unit of Experimental Surgical Pathology University Hospital of Pisa Pisa Italy

Department of Surgical and Peroperative Sciences Umeå University Umeå Sweden

Digestive and Liver Disease Unit 'Sapienza' University of Rome Rome Italy

Dipartimento di Medicina Clinica E Chirurgia Federico 2 Univeristy Naples Italy

Division of Aging Department of Medicine Brigham and Women's Hospital and Harvard Medical School Boston Massachusetts USA

Division of Biomedical Statistics and Informatics Department of Health Sciences Research Mayo Clinic Rochester Minnesota USA

Division of Cancer Control and Population Sciences National Cancer Institute National Institutes of Health Bethesda Maryland USA

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

Division of Cancer Epidemiology German Cancer Research Center Heidelberg Germany

Division of Clinical Epidemiology and Aging Research German Cancer Research Center Heidelberg Germany

Division of Epidemiology Department of Health Sciences Research Mayo Clinic Rochester Minnesota USA

Division of Epidemiology Vanderbilt University Medical Center Nashville Tennessee USA

Division of Gastroenterology and Research Laboratory IRCCS Scientific Institute and Regional General Hospital Casa Sollievo della Sofferenza San Giovanni Rotondo Italy

Division of Preventive Medicine Department of Medicine Brigham and Women's Hospital and Harvard Medical School Boston Massachusetts USA

Division of Preventive Oncology German Cancer Research Center Heidelberg Germany

Division of Public Health Sciences Fred Hutchinson Cancer Research Center Seattle Washington USA

Epidemiology and Prevention Unit Fondazione IRCCS Istituto Nazionale dei Tumori Milan Italy

Epidemiology Research Program American Cancer Society Atlanta Georgia USA

Gastroenterology and Gastrointestinal Endoscopy Unit Vita Salute San Raffaele University IRCCS San Raffaele Scientific Institute Milan Italy

Genetic and Molecular Epidemiology Group CNIO Spanish National Cancer Research Centre Madrid Spain

Genomic Epidemiology Group German Cancer Research Center Heidelberg Germany

German Cancer Consortium Heidelberg Germany

Glickman Urological and Kidney Institute Cleveland Clinic Cleveland Ohio USA

Group Health Research Institute Seattle Washington USA

Harvard Medical School Boston Massachusetts USA

Harvard School of Public Health Boston Massachusetts USA

Hellenic Health Foundation Athens Greece

Hospital del Mar Institute of Medical Research Barcelona Spain

IGR F 94805 Villejuif France

Inserm Centre for Research in Epidemiology and Population Health U1018 Nutrition Hormones and Women's Health Team F 94805 Villejuif France

Institute of Cancer Epidemiology Danish Cancer Society Copenhagen Denmark

International Agency for Research on Cancer Lyon France

Johns Hopkins Bloomberg School of Public Health Baltimore Maryland USA

Julius Center for Health Sciences and Primary Care University Medical Center Utrecht Utrecht The Netherlands

Laboratory for Experimental Oncology and Radiobiology Academic Medical Center University of Amsterdam Amsterdam The Netherlands

Laboratory of Medicine and Pathology University of Minnesota Minneapolis Minnesota USA

Laboratory of Pharmacogenomics Biomedical Center Faculty of Medicine in Pilsen Charles University Prague Pilsen Czech Republic

Laboratory of Translational Genomics Division of Cancer Epidemiology and Genetics National Cancer Institute National Institutes of Health Bethesda Maryland USA

Lunenfeld Tanenbaum Research Institute Mount Sinai Hospital Toronto Ontario Canada

Massachusetts Veteran's Epidemiology Research and Information Center Geriatric Research Education and Clinical Center Veterans Affairs Boston Healthcare System Boston Massachusetts USA

National Institute for Health and Welfare Department of Chronic Disease Prevention Helsinki Finland

National Institute for Health Research Liverpool Pancreas Biomedical Research Unit University of Liverpool Liverpool United Kingdom

National School of Public Health Athens Greece

New York University Cancer Institute New York New York USA

Oncology Department ASL1 Massa Carrara Massa Carrara Italy

Pancreas Unit Department of Digestive Diseases and Internal Medicine Sant'Orsola Malpighi Hospital Bologna Italy

Prevention and Cancer Control Cancer Care Ontario Toronto Ontario Canada

Preventive Medicine University of Southern California Los Angeles California USA

Public Health and Participation Directorate Asturias Spain

School of Clinical Medicine University of Cambridge Cambridge United Kingdom

School of Medicine Universitat Autònoma de Barcelona Barcelona Spain

Southwest Oncology Group Statistical Center Fred Hutchinson Cancer Research Center Seattle Washington USA

Unit of Nutrition and Cancer Cancer Epidemiology Research Program Bellvitge Biomedical Research Institute Barcelona Spain

University Paris Sud UMRS 1018 F 94805 Villejuif France

Vanderbilt Epidemiology Center Vanderbilt Ingram Cancer Center Vanderbilt University Medical Center Nashville Tennessee USA

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