GWAS meta-analysis of 16 790 patients with Barrett's oesophagus and oesophageal adenocarcinoma identifies 16 novel genetic risk loci and provides insights into disease aetiology beyond the single marker level

Julia Schröder^#¹, Laura Chegwidden^#², Carlo Maj^#³, Jan Gehlen³, Jan Speller⁴, Anne C Böhmer¹, Oleg Borisov⁵, Timo Hess³, Nicole Kreuser⁶, Marino Venerito⁷, Hakan Alakus⁸, Andrea May⁹, Christian Gerges¹⁰, Thomas Schmidt⁸, Rene Thieme⁶, Dominik Heider¹¹, Axel M Hillmer¹², Julian Reingruber³, Orestis Lyros⁶, Arne Dietrich⁶, Albrecht Hoffmeister¹³, Matthias Mehdorn⁶, Florian Lordick¹⁴, Gertraud Stocker¹⁴, Michael Hohaus¹⁵, Daniel Reim¹⁶, Jennis Kandler¹⁷, Michaela Müller¹⁸, Alanna Ebigbo¹⁹, Claudia Fuchs⁸, Christiane J Bruns⁸, Arnulf H Hölscher²⁰, Hauke Lang²¹, Peter P Grimminger²¹, Dani Dakkak²², Yogesh Vashist²³, Sandra May²⁴, Siegfried Görg²⁵, Andre Franke²⁴, David Ellinghaus²⁴, Sara Galavotti², Lothar Veits²⁶, Josef Weismüller²⁷, Jens Dommermuth²⁷, Udo Benner²⁷, Thomas Rösch²⁸, Helmut Messmann¹⁹, Brigitte Schumacher²², Horst Neuhaus¹⁰, Carsten Schmidt^{29

30}, Thaddäus T Wissinowski³¹, Markus M Nöthen¹; Wellcome Trust Case Control Consortium 2 (WTCCC2); Esophageal Adenocarcinoma Genetics Consortium (EAGLE); Barrett's and Esophageal Adenocarcinoma Consortium (BEACON); Jing Dong³², Jue-Sheng Ong³³, Matthew F Buas³⁴, Aaron P Thrift³⁵, Thomas L Vaughan³⁶, Ian Tomlinson³⁷, David C Whiteman³⁸, Rebecca Claire Fitzgerald³⁹, Janusz Jankowski⁴⁰, Michael Vieth²⁶, Andreas Mayr⁴, Puya Gharahkhani³³, Stuart MacGregor³³, Ines Gockel^#⁶, Claire Palles^#², Johannes Schumacher^#⁴¹

Collaborators, Affiliations

Collaborators

Peter Donnelly, Ines Barroso, Jenefer M Blackwell, Elvira Bramon, Matthew A Brown, Juan P Casas, Aiden Corvin, Panos Deloukas, Audrey Duncanson, Janusz Jankowski, Hugh S Markus, Christopher G Mathew, Colin Na Palmer, Robert Plomin, Anna Rautanen, Stephen J Sawcer, Richard C Trembath, Ananth C Viswanathan, Nicholas W Wood, Chris C A Spencer, Gavin Band, Céline Bellenguez, Colin Freeman, Garrett Hellenthal, Eleni Giannoulatou, Matti Pirinen, Richard Pearson, Amy Strange, Zhan Su, Damjan Vukcevic, Peter Donnelly, Cordelia Langford, Sarah E Hunt, Sarah Edkins, Rhian Gwilliam, Hannah Blackburn, Suzannah J Bumpstead, Serge Dronov, Matthew Gillman, Emma Gray, Naomi Hammond, Alagurevathi Jayakumar, Owen T McCann, Jennifer Liddle, Simon C Potter, Radhi Ravindrarajah, Michelle Ricketts, Matthew Waller, Paul Weston, Sara Widaa, Pamela Whittaker, Ines Barroso, Panos Deloukas, Christopher G Mathew, Jenefer M Blackwell, Matthew A Brown, Aiden Corvin, Chris Ca Spencer, Peter Isaacs, Conrad Beckett, Sue Cullen, David Hobday, Ameet Dhar, Deepak Kejariwal, James Shutt, Ian Sargeant, Konrad Koss, Charles Grimley, Hugh Barr, Helen Winter, Andrew Dixon, Hugh McMurty, Matthew Johnson, Haythem Ali, Sandro Lazon-Miller, Stuart Paterson, Ian Beales, Chris MacDonald, Matt Rutter, Alex Moran, Chris Haig, Krish Ragunath, Siba Senapati, Pradeep Bhandari, Saj Wajed, Salma Alam, Mark Farrent, Yeng Ang, Nigel Trudgill, Mark Smith, Keith George, Arvind Ramadas, Simon Panter, Vinod Patel, Laurence Lovat, Mark Kelly, Praful Patel, Stephen Falk, Chuka Nwokolo, John deCaestecker, Subramaniam Ramakrishnan, Yang Eng, Sean Kelly, Art Tucker, Paul Mullins, Hans Prenen, Janusz Jankowski, Marilie D Gammon, Douglas A Corley, Nicholas J Shaheen, Nigel C Bird, Laura J Hardie, Liam J Murray, Brian J Reid, Wong-Ho Chow, Harvey A Risch, Weimin Ye, Geoffrey Liu, Leslie Bernstein, Prasad Iyer, Lesley Anderson, Jesper Lagergren, Rebecca Fitzgerald, Anna H Wu, David C Whiteman, Thomas L Vaughan

Affiliations

¹ Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany.
² Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK.
³ Center for Human Genetics, University Hospital of Marburg, Marburg, Germany.
⁴ Institute of Medical Biometrics, Informatics and Epidemiology (IMBIE), Medical Faculty, University of Bonn, Bonn, Germany.
⁵ Institute for Genomic Statistics and Bioinformatics, Medical Faculty, University of Bonn, Bonn, Germany.
⁶ Department of Visceral, Transplant, Thoracic and Vascular Surgery, University Hospital of Leipzig, Leipzig, Germany.
⁷ Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University, Magdeburg, Germany.
⁸ Department of General, Visceral, Cancer and Transplantation Surgery, University Hospital of Cologne, Cologne, Germany.
⁹ Department of Gastroenterology, Oncology and Pneumology, Asklepios Paulinen Clinic Wiesbaden, Wiesbaden, Germany.
¹⁰ Department of Internal Medicine II, Evangelisches Krankenhaus Dusseldorf, Dusseldorf, Germany.
¹¹ Department of Mathematics and Computer Science, University of Marburg, Marburg, Germany.
¹² Institute of Pathology, Faculty of Medicine and University Hospital Cologne, University Hospital Cologne, Cologne, Germany.
¹³ Department of Gastroenterology, University of Leipzig, Leipzig, Germany.
¹⁴ University Cancer Center Leipzig (UCCL), Leipzig University Medical Center, Leipzig, Germany.
¹⁵ Department for General and Visceral Surgery, Städt. Klinikum Dresden Friedrichstadt, Dresden, Germany.
¹⁶ Department of Surgery, Technical University of Munich, School of Medicine, Klinikum Rechts der Isar, München, Germany.
¹⁷ Clinic for Gastroenterology, Hepatology and Infectious Diseases, University Hospital Dusseldorf, Medical Faculty of Heinrich Heine University Dusseldorf, Dusseldorf, Germany.
¹⁸ Department of Gastroenterology, Endocrinology, Metabolism and Infectiology, University Hospital Marburg and Philipps University, Marburg, Germany.
¹⁹ Department of Gastroenterology, University Hospital Augsburg, Augsburg, Germany.
²⁰ Department for General, Visceral and Trauma Surgery, Elisabeth-Krankenhaus-Essen GmbH, Essen, Germany.
²¹ Department of General, Visceral and Transplant Surgery, University Medical Center, University of Mainz, Mainz, Germany.
²² Department of Internal Medicine and Gastroenterology, Elisabeth Hospital Essen, Essen, Germany.
²³ Medias Klinikum, Burghausen, Germany.
²⁴ Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany.
²⁵ Institute of Transfusion Medicine, University Hospital of Schleswig-Holstein, Lübeck/Kiel, Germany.
²⁶ Institute of Pathology, Friedrich-Alexander-Universiät Erlangen-Nürnberg, Klinikum Bayreuth, Bayreuth, Germany.
²⁷ Gastroenterologische Gemeinschaftspraxis, Koblenz, Germany.
²⁸ Department of Interdisciplinary Endoscopy, University Hospital Hamburg-Eppendorf, Hamburg, Germany.
²⁹ Medical Clinic II (Gastroenterology, Hepatology, Endocrinology, Diabetology and Infektiology), Klinikum Fulda, University Medicine Marburg-Campus Fulda, Fulda, Germany.
³⁰ Medical Faculty, Friedrich Schiller University Jena, Jena, Germany.
³¹ Center for Inner Medicine II, Klinikum Chemnitz gGmbH, Chemnitz, Germany.
³² Division of Hematology and Oncology, Department of Medicine, Cancer Center, and Genomic Sciences & Precision Medicine Center, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
³³ Statistical Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
³⁴ Department of Cancer Prevention and Control, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA.
³⁵ Section of Epidemiology and Population Sciences, Department of Medicine, Baylor College of Medicine, Houston, Texas, USA.
³⁶ Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
³⁷ Edinburgh Cancer Research Centre, IGMM, University of Edinburgh, Edinburgh, UK.
³⁸ Cancer Control, Department of Population Health, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
³⁹ Medical Research Council (MRC) Cancer Unit, Hutchison-MRC Research Centre, University of Cambridge, Cambridge, Cambridgeshire, UK.
⁴⁰ Comprehensive Clinical Trials Unit, University College London, London, UK.
⁴¹ Center for Human Genetics, University Hospital of Marburg, Marburg, Germany johannes.schumacher@uni-marburg.de.

^# Contributed equally.

PMID: 35882562
DOI: 10.1136/gutjnl-2021-326698

Meta-Analysis

GWAS meta-analysis of 16 790 patients with Barrett's oesophagus and oesophageal adenocarcinoma identifies 16 novel genetic risk loci and provides insights into disease aetiology beyond the single marker level

Julia Schröder et al. Gut. 2023 Apr.

. 2023 Apr;72(4):612-623.

doi: 10.1136/gutjnl-2021-326698. Epub 2022 Jul 26.

Authors

Collaborators

Peter Donnelly, Ines Barroso, Jenefer M Blackwell, Elvira Bramon, Matthew A Brown, Juan P Casas, Aiden Corvin, Panos Deloukas, Audrey Duncanson, Janusz Jankowski, Hugh S Markus, Christopher G Mathew, Colin Na Palmer, Robert Plomin, Anna Rautanen, Stephen J Sawcer, Richard C Trembath, Ananth C Viswanathan, Nicholas W Wood, Chris C A Spencer, Gavin Band, Céline Bellenguez, Colin Freeman, Garrett Hellenthal, Eleni Giannoulatou, Matti Pirinen, Richard Pearson, Amy Strange, Zhan Su, Damjan Vukcevic, Peter Donnelly, Cordelia Langford, Sarah E Hunt, Sarah Edkins, Rhian Gwilliam, Hannah Blackburn, Suzannah J Bumpstead, Serge Dronov, Matthew Gillman, Emma Gray, Naomi Hammond, Alagurevathi Jayakumar, Owen T McCann, Jennifer Liddle, Simon C Potter, Radhi Ravindrarajah, Michelle Ricketts, Matthew Waller, Paul Weston, Sara Widaa, Pamela Whittaker, Ines Barroso, Panos Deloukas, Christopher G Mathew, Jenefer M Blackwell, Matthew A Brown, Aiden Corvin, Chris Ca Spencer, Peter Isaacs, Conrad Beckett, Sue Cullen, David Hobday, Ameet Dhar, Deepak Kejariwal, James Shutt, Ian Sargeant, Konrad Koss, Charles Grimley, Hugh Barr, Helen Winter, Andrew Dixon, Hugh McMurty, Matthew Johnson, Haythem Ali, Sandro Lazon-Miller, Stuart Paterson, Ian Beales, Chris MacDonald, Matt Rutter, Alex Moran, Chris Haig, Krish Ragunath, Siba Senapati, Pradeep Bhandari, Saj Wajed, Salma Alam, Mark Farrent, Yeng Ang, Nigel Trudgill, Mark Smith, Keith George, Arvind Ramadas, Simon Panter, Vinod Patel, Laurence Lovat, Mark Kelly, Praful Patel, Stephen Falk, Chuka Nwokolo, John deCaestecker, Subramaniam Ramakrishnan, Yang Eng, Sean Kelly, Art Tucker, Paul Mullins, Hans Prenen, Janusz Jankowski, Marilie D Gammon, Douglas A Corley, Nicholas J Shaheen, Nigel C Bird, Laura J Hardie, Liam J Murray, Brian J Reid, Wong-Ho Chow, Harvey A Risch, Weimin Ye, Geoffrey Liu, Leslie Bernstein, Prasad Iyer, Lesley Anderson, Jesper Lagergren, Rebecca Fitzgerald, Anna H Wu, David C Whiteman, Thomas L Vaughan

Affiliations

¹ Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany.
² Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK.
³ Center for Human Genetics, University Hospital of Marburg, Marburg, Germany.
⁴ Institute of Medical Biometrics, Informatics and Epidemiology (IMBIE), Medical Faculty, University of Bonn, Bonn, Germany.
⁵ Institute for Genomic Statistics and Bioinformatics, Medical Faculty, University of Bonn, Bonn, Germany.
⁶ Department of Visceral, Transplant, Thoracic and Vascular Surgery, University Hospital of Leipzig, Leipzig, Germany.
⁷ Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University, Magdeburg, Germany.
⁸ Department of General, Visceral, Cancer and Transplantation Surgery, University Hospital of Cologne, Cologne, Germany.
⁹ Department of Gastroenterology, Oncology and Pneumology, Asklepios Paulinen Clinic Wiesbaden, Wiesbaden, Germany.
¹⁰ Department of Internal Medicine II, Evangelisches Krankenhaus Dusseldorf, Dusseldorf, Germany.
¹¹ Department of Mathematics and Computer Science, University of Marburg, Marburg, Germany.
¹² Institute of Pathology, Faculty of Medicine and University Hospital Cologne, University Hospital Cologne, Cologne, Germany.
¹³ Department of Gastroenterology, University of Leipzig, Leipzig, Germany.
¹⁴ University Cancer Center Leipzig (UCCL), Leipzig University Medical Center, Leipzig, Germany.
¹⁵ Department for General and Visceral Surgery, Städt. Klinikum Dresden Friedrichstadt, Dresden, Germany.
¹⁶ Department of Surgery, Technical University of Munich, School of Medicine, Klinikum Rechts der Isar, München, Germany.
¹⁷ Clinic for Gastroenterology, Hepatology and Infectious Diseases, University Hospital Dusseldorf, Medical Faculty of Heinrich Heine University Dusseldorf, Dusseldorf, Germany.
¹⁸ Department of Gastroenterology, Endocrinology, Metabolism and Infectiology, University Hospital Marburg and Philipps University, Marburg, Germany.
¹⁹ Department of Gastroenterology, University Hospital Augsburg, Augsburg, Germany.
²⁰ Department for General, Visceral and Trauma Surgery, Elisabeth-Krankenhaus-Essen GmbH, Essen, Germany.
²¹ Department of General, Visceral and Transplant Surgery, University Medical Center, University of Mainz, Mainz, Germany.
²² Department of Internal Medicine and Gastroenterology, Elisabeth Hospital Essen, Essen, Germany.
²³ Medias Klinikum, Burghausen, Germany.
²⁴ Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany.
²⁵ Institute of Transfusion Medicine, University Hospital of Schleswig-Holstein, Lübeck/Kiel, Germany.
²⁶ Institute of Pathology, Friedrich-Alexander-Universiät Erlangen-Nürnberg, Klinikum Bayreuth, Bayreuth, Germany.
²⁷ Gastroenterologische Gemeinschaftspraxis, Koblenz, Germany.
²⁸ Department of Interdisciplinary Endoscopy, University Hospital Hamburg-Eppendorf, Hamburg, Germany.
²⁹ Medical Clinic II (Gastroenterology, Hepatology, Endocrinology, Diabetology and Infektiology), Klinikum Fulda, University Medicine Marburg-Campus Fulda, Fulda, Germany.
³⁰ Medical Faculty, Friedrich Schiller University Jena, Jena, Germany.
³¹ Center for Inner Medicine II, Klinikum Chemnitz gGmbH, Chemnitz, Germany.
³² Division of Hematology and Oncology, Department of Medicine, Cancer Center, and Genomic Sciences & Precision Medicine Center, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
³³ Statistical Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
³⁴ Department of Cancer Prevention and Control, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA.
³⁵ Section of Epidemiology and Population Sciences, Department of Medicine, Baylor College of Medicine, Houston, Texas, USA.
³⁶ Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
³⁷ Edinburgh Cancer Research Centre, IGMM, University of Edinburgh, Edinburgh, UK.
³⁸ Cancer Control, Department of Population Health, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
³⁹ Medical Research Council (MRC) Cancer Unit, Hutchison-MRC Research Centre, University of Cambridge, Cambridge, Cambridgeshire, UK.
⁴⁰ Comprehensive Clinical Trials Unit, University College London, London, UK.
⁴¹ Center for Human Genetics, University Hospital of Marburg, Marburg, Germany johannes.schumacher@uni-marburg.de.

^# Contributed equally.

PMID: 35882562
DOI: 10.1136/gutjnl-2021-326698

Abstract

Objective: Oesophageal cancer (EC) is the sixth leading cause of cancer-related deaths. Oesophageal adenocarcinoma (EA), with Barrett's oesophagus (BE) as a precursor lesion, is the most prevalent EC subtype in the Western world. This study aims to contribute to better understand the genetic causes of BE/EA by leveraging genome wide association studies (GWAS), genetic correlation analyses and polygenic risk modelling.

Design: We combined data from previous GWAS with new cohorts, increasing the sample size to 16 790 BE/EA cases and 32 476 controls. We also carried out a transcriptome wide association study (TWAS) using expression data from disease-relevant tissues to identify BE/EA candidate genes. To investigate the relationship with reported BE/EA risk factors, a linkage disequilibrium score regression (LDSR) analysis was performed. BE/EA risk models were developed combining clinical/lifestyle risk factors with polygenic risk scores (PRS) derived from the GWAS meta-analysis.

Results: The GWAS meta-analysis identified 27 BE and/or EA risk loci, 11 of which were novel. The TWAS identified promising BE/EA candidate genes at seven GWAS loci and at five additional risk loci. The LDSR analysis led to the identification of novel genetic correlations and pointed to differences in BE and EA aetiology. Gastro-oesophageal reflux disease appeared to contribute stronger to the metaplastic BE transformation than to EA development. Finally, combining PRS with BE/EA risk factors improved the performance of the risk models.

Conclusion: Our findings provide further insights into BE/EA aetiology and its relationship to risk factors. The results lay the foundation for future follow-up studies to identify underlying disease mechanisms and improving risk prediction.

Keywords: BARRETT'S OESOPHAGUS; CANCER GENETICS; GENOTYPE; OESOPHAGEAL CANCER.

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Competing interests: None declared.

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GWAS meta-analysis of 16 790 patients with Barrett's oesophagus and oesophageal adenocarcinoma identifies 16 novel genetic risk loci and provides insights into disease aetiology beyond the single marker level

Collaborators

Affiliations

GWAS meta-analysis of 16 790 patients with Barrett's oesophagus and oesophageal adenocarcinoma identifies 16 novel genetic risk loci and provides insights into disease aetiology beyond the single marker level

Authors

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Affiliations

Abstract

Conflict of interest statement

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