Although 21 pancreatic cancer susceptibility loci have been identified in individuals of European ancestry through genome-wide association studies (GWASs), much of the heritability of pancreatic cancer risk remains unidentified. A recessive genetic model could be a powerful tool for identifying additional risk variants. To discover recessively inherited pancreatic cancer risk loci, we performed a re-analysis of the largest pancreatic cancer GWAS, the Pancreatic Cancer Cohort Consortium (PanScan) and the Pancreatic Cancer Case-Control Consortium (PanC4), including 8,769 cases and 7,055 controls of European ancestry. Six single nucleotide polymorphisms (SNPs) showed associations with pancreatic cancer risk according to a recessive model of inheritance. We replicated these variants in 3,212 cases and 3,470 controls collected from the PANcreatic Disease ReseArch (PANDoRA) consortium. The results of the meta-analyses confirmed that rs4626538 (7q32.2), rs7008921 (8p23.2) and rs147904962 (17q21.31) showed specific recessive effects (p<10-5) compared with the additive effects (p>10-3), although none of the six SNPs reached the conventional threshold for genome-wide significance (p < 5×10-8). Additional bioinformatic analysis explored the functional annotations of the SNPs and indicated a possible relationship between rs36018702 and expression of the BCL2L11 and BUB1 genes, which are known to be involved in pancreatic biology. Our findings, while not conclusive, indicate the importance of considering non-additive genetic models when performing GWAS analysis. The SNPs associated with pancreatic cancer in this study could be used for further meta-analysis for recessive association of SNPs and pancreatic cancer risk and might be a useful addiction to improve the performance of polygenic risk scores.

1st Department of Medicine University of Szeged Szeged Hungary

1st Faculty of Medicine Institute of Biology and Medical Genetics Prague Czechia

1st Propaedeutic University Surgery Clinic Hippocratio General Hospital Medical School National and Kapodistrian University of Athens Athens Greece

Applied Research on Cancer Net Research Center University and Hospital Trust of Verona Verona Italy

Biomedical Center Faculty of Medicine in Pilsen Charles University Pilsen Czechia

Blood Transfusion Service Children's Hospital Azienda Ospedaliero Universitaria Meyer Florence Italy

Centre for Surgical Oncology Medias Klinikum Burghausen Burghausen Germany

Centre for Translational Medicine Department of Medicine University of Szeged Szeged Hungary

Department for Determinants of Chronic Diseases Bilthoven 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 Digestive Tract Diseases Medical University of Lodz Lodz Poland

Department of Gastroenterology Institute for Digestive Research Medical Academy Lithuanian University of Health Sciences Kaunas Lithuania

Department of General and Pancreatic Surgery The Pancreas Institute University and Hospital Trust of Verona Verona Italy

Department of General Surgery University of Heidelberg Heidelberg Germany

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

Department of Hematology Transplantation and Internal Medicine Medical University of Warsaw Warsaw Poland

Department of Internal Medicine San Carlo Hospital Potenza Italy

Department of Medical Oncology Cancer Center Amsterdam Amsterdam University Medical Centers University of Amsterdam Amsterdam Netherlands

Department of Medicine Padua University Hospital Padua Italy

Department of Molecular and Clinical Cancer Medicine University of Liverpool Liverpool United Kingdom

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

Department of Oncology Faculty of Medicine and Dentistry Palacky University Olomouc and University Hospital Olomouc Olomouc Czechia

Department of Radiology and Oncology Institute of Cancer of São Paulo São Paulo Brazil

Department of Surgery 1 Faculty of Medicine and Dentistry Palacky University Olomouc and University Hospital Olomouc Olomouc Czechia

Department of Surgery Cancer Center Amsterdam Amsterdam University Medical Centers University of Amsterdam Amsterdam Netherlands

Department of Surgery Dipartimento di Scienze Chirurgiche Oncologiche e Gastroenterologiche Padua University Hospital Padua Italy

Department of Surgery Faculty Hospital Kralovske Vinohrady and 3rd Faculty of Medicine Charles University Prague Czechia

Department of Surgery Medical School University of Pécs Pécs Hungary

Department of Surgery University Hospital Brno Bohunice Faculty of Medicine Masaryk University Brno Czechia

Digestive and Liver Disease Unit Sant' Andrea Hospital Rome Italy

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

Division of Experimental Oncology Gastroenterology and Gastrointestinal Endoscopy Unit Vita Salute San Raffaele University Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele Scientific Institute Milan Italy

Division of Gastroenterology and Digestive Endoscopy Department of Gastroenterology Humanitas Clinical and Research Center Istituto di Ricovero e Cura a Carattere Scientifico Milan Italy

Division of Gastroenterology and Research Laboratory Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Casa Sollievo della Sofferenza San Giovanni Rotondo Italy

Division of General and Transplant Surgery Pisa University Hospital Pisa Italy

Division of Preventive Oncology German Cancer Research Center Heidelberg Germany

Endoscopic Surgery Department Hippocratio General Hospital of Athens Athens Greece

Faculty of Medicine and Biomedical Center in Pilsen Charles University Pilsen Czechia

Faculty of Medicine and Psychology Sapienza University of Rome Rome Italy

Faculty of Medicine University of São Paulo São Paulo Brazil

General Surgery Department of Translational Research and New Technologies in Medicine and Surgery University of Pisa Pisa Italy

Genomic Epidemiology Group German Cancer Research Center Heidelberg Germany

German Cancer Consortium Heidelberg Germany

Institute for Translational Medicine Medical School University of Pécs Pécs Hungary

Institute of Molecular and Translational Medicine Faculty of Medicine and Dentistry Palacky University Olomouc Olomouc Czechia

Laboratory for Applied Science and Technology in Health Carlos Chagas Institute Curitiba Brazil

Medical Faculty Heidelberg University of Heidelberg Heidelberg Germany

Oncological Department Oncological Unit of Massa Carrara Azienda Unità Sanitaria Locale Toscana Nord Ovest Carrara Italy

Pancreato Biliary Endoscopy and Endosonography Division Pancreas Translational and Clinical Research Center San Raffaele Scientific Institute Istituto di Ricovero e Cura a Carattere Scientifico Milan Italy

Pándy Kálmán Hospital of Békés County Gyula Hungary

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