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.

Humans Barrett Esophagus / pathology Genome-Wide Association Study Esophageal Neoplasms / pathology Adenocarcinoma / pathology
BARRETT'S OESOPHAGUS CANCER GENETICS GENOTYPE OESOPHAGEAL CANCER

Journal

Gut
ISSN: 1468-3288
Titre abrégé: Gut
Pays: England
ID NLM: 2985108R

Informations de publication

Date de publication:
04 2023
Historique:
received: 05 12 2021
accepted: 07 07 2022
pubmed: 27 7 2022
medline: 10 3 2023
entrez: 26 7 2022
Statut: ppublish

Résumé

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. 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. 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. 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.

Identifiants

DOI: 10.1136/gutjnl-2021-326698 PMID: 35882562
pubmed: 35882562
pii: gutjnl-2021-326698
doi: 10.1136/gutjnl-2021-326698
doi:

Types de publication

Meta-Analysis Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

612-623

Investigateurs

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

Informations de copyright

© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.

Déclaration de conflit d'intérêts

Competing interests: None declared.

Auteurs

Julia Schröder (J)

Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany.
ORCID: 0000-0002-5278-7904

Laura Chegwidden (L)

Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK.

Carlo Maj (C)

Center for Human Genetics, University Hospital of Marburg, Marburg, Germany.

Jan Gehlen (J)

Center for Human Genetics, University Hospital of Marburg, Marburg, Germany.

Jan Speller (J)

Institute of Medical Biometrics, Informatics and Epidemiology (IMBIE), Medical Faculty, University of Bonn, Bonn, Germany.

Anne C Böhmer (AC)

Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany.

Oleg Borisov (O)

Institute for Genomic Statistics and Bioinformatics, Medical Faculty, University of Bonn, Bonn, Germany.

Timo Hess (T)

Center for Human Genetics, University Hospital of Marburg, Marburg, Germany.
ORCID: 0000-0003-2778-4274

Nicole Kreuser (N)

Department of Visceral, Transplant, Thoracic and Vascular Surgery, University Hospital of Leipzig, Leipzig, Germany.

Marino Venerito (M)

Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University, Magdeburg, Germany.

Hakan Alakus (H)

Department of General, Visceral, Cancer and Transplantation Surgery, University Hospital of Cologne, Cologne, Germany.

Andrea May (A)

Department of Gastroenterology, Oncology and Pneumology, Asklepios Paulinen Clinic Wiesbaden, Wiesbaden, Germany.

Christian Gerges (C)

Department of Internal Medicine II, Evangelisches Krankenhaus Dusseldorf, Dusseldorf, Germany.

Thomas Schmidt (T)

Department of General, Visceral, Cancer and Transplantation Surgery, University Hospital of Cologne, Cologne, Germany.

Rene Thieme (R)

Department of Visceral, Transplant, Thoracic and Vascular Surgery, University Hospital of Leipzig, Leipzig, Germany.

Dominik Heider (D)

Department of Mathematics and Computer Science, University of Marburg, Marburg, Germany.

Axel M Hillmer (AM)

Institute of Pathology, Faculty of Medicine and University Hospital Cologne, University Hospital Cologne, Cologne, Germany.

Julian Reingruber (J)

Center for Human Genetics, University Hospital of Marburg, Marburg, Germany.

Orestis Lyros (O)

Department of Visceral, Transplant, Thoracic and Vascular Surgery, University Hospital of Leipzig, Leipzig, Germany.

Arne Dietrich (A)

Department of Visceral, Transplant, Thoracic and Vascular Surgery, University Hospital of Leipzig, Leipzig, Germany.

Albrecht Hoffmeister (A)

Department of Gastroenterology, University of Leipzig, Leipzig, Germany.

Matthias Mehdorn (M)

Department of Visceral, Transplant, Thoracic and Vascular Surgery, University Hospital of Leipzig, Leipzig, Germany.

Florian Lordick (F)

University Cancer Center Leipzig (UCCL), Leipzig University Medical Center, Leipzig, Germany.

Gertraud Stocker (G)

University Cancer Center Leipzig (UCCL), Leipzig University Medical Center, Leipzig, Germany.

Michael Hohaus (M)

Department for General and Visceral Surgery, Städt. Klinikum Dresden Friedrichstadt, Dresden, Germany.

Daniel Reim (D)

Department of Surgery, Technical University of Munich, School of Medicine, Klinikum Rechts der Isar, München, Germany.

Jennis Kandler (J)

Clinic for Gastroenterology, Hepatology and Infectious Diseases, University Hospital Dusseldorf, Medical Faculty of Heinrich Heine University Dusseldorf, Dusseldorf, Germany.

Michaela Müller (M)

Department of Gastroenterology, Endocrinology, Metabolism and Infectiology, University Hospital Marburg and Philipps University, Marburg, Germany.

Alanna Ebigbo (A)

Department of Gastroenterology, University Hospital Augsburg, Augsburg, Germany.

Claudia Fuchs (C)

Department of General, Visceral, Cancer and Transplantation Surgery, University Hospital of Cologne, Cologne, Germany.

Christiane J Bruns (CJ)

Department of General, Visceral, Cancer and Transplantation Surgery, University Hospital of Cologne, Cologne, Germany.

Arnulf H Hölscher (AH)

Department for General, Visceral and Trauma Surgery, Elisabeth-Krankenhaus-Essen GmbH, Essen, Germany.

Hauke Lang (H)

Department of General, Visceral and Transplant Surgery, University Medical Center, University of Mainz, Mainz, Germany.

Peter P Grimminger (PP)

Department of General, Visceral and Transplant Surgery, University Medical Center, University of Mainz, Mainz, Germany.

Dani Dakkak (D)

Department of Internal Medicine and Gastroenterology, Elisabeth Hospital Essen, Essen, Germany.

Yogesh Vashist (Y)

Medias Klinikum, Burghausen, Germany.

Sandra May (S)

Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany.

Siegfried Görg (S)

Institute of Transfusion Medicine, University Hospital of Schleswig-Holstein, Lübeck/Kiel, Germany.

Andre Franke (A)

Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany.

David Ellinghaus (D)

Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany.
ORCID: 0000-0002-4332-6110

Sara Galavotti (S)

Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK.

Lothar Veits (L)

Institute of Pathology, Friedrich-Alexander-Universiät Erlangen-Nürnberg, Klinikum Bayreuth, Bayreuth, Germany.

Josef Weismüller (J)

Gastroenterologische Gemeinschaftspraxis, Koblenz, Germany.

Jens Dommermuth (J)

Gastroenterologische Gemeinschaftspraxis, Koblenz, Germany.

Udo Benner (U)

Gastroenterologische Gemeinschaftspraxis, Koblenz, Germany.

Thomas Rösch (T)

Department of Interdisciplinary Endoscopy, University Hospital Hamburg-Eppendorf, Hamburg, Germany.
ORCID: 0000-0003-2270-2495

Helmut Messmann (H)

Department of Gastroenterology, University Hospital Augsburg, Augsburg, Germany.

Brigitte Schumacher (B)

Department of Internal Medicine and Gastroenterology, Elisabeth Hospital Essen, Essen, Germany.

Horst Neuhaus (H)

Department of Internal Medicine II, Evangelisches Krankenhaus Dusseldorf, Dusseldorf, Germany.

Carsten Schmidt (C)

Medical Clinic II (Gastroenterology, Hepatology, Endocrinology, Diabetology and Infektiology), Klinikum Fulda, University Medicine Marburg-Campus Fulda, Fulda, Germany.
Medical Faculty, Friedrich Schiller University Jena, Jena, Germany.

Thaddäus T Wissinowski (TT)

Center for Inner Medicine II, Klinikum Chemnitz gGmbH, Chemnitz, Germany.

Markus M Nöthen (MM)

Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany.

Jing Dong (J)

Division of Hematology and Oncology, Department of Medicine, Cancer Center, and Genomic Sciences & Precision Medicine Center, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.

Jue-Sheng Ong (JS)

Statistical Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
ORCID: 0000-0002-6062-710X

Matthew F Buas (MF)

Department of Cancer Prevention and Control, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA.

Aaron P Thrift (AP)

Section of Epidemiology and Population Sciences, Department of Medicine, Baylor College of Medicine, Houston, Texas, USA.
ORCID: 0000-0002-0084-5308

Thomas L Vaughan (TL)

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

Ian Tomlinson (I)

Edinburgh Cancer Research Centre, IGMM, University of Edinburgh, Edinburgh, UK.

David C Whiteman (DC)

Cancer Control, Department of Population Health, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.

Rebecca Claire Fitzgerald (RC)

Medical Research Council (MRC) Cancer Unit, Hutchison-MRC Research Centre, University of Cambridge, Cambridge, Cambridgeshire, UK.

Janusz Jankowski (J)

Comprehensive Clinical Trials Unit, University College London, London, UK.

Michael Vieth (M)

Institute of Pathology, Friedrich-Alexander-Universiät Erlangen-Nürnberg, Klinikum Bayreuth, Bayreuth, Germany.

Andreas Mayr (A)

Institute of Medical Biometrics, Informatics and Epidemiology (IMBIE), Medical Faculty, University of Bonn, Bonn, Germany.

Puya Gharahkhani (P)

Statistical Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.

Stuart MacGregor (S)

Statistical Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.

Ines Gockel (I)

Department of Visceral, Transplant, Thoracic and Vascular Surgery, University Hospital of Leipzig, Leipzig, Germany.

Claire Palles (C)

Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK.

Johannes Schumacher (J)

Center for Human Genetics, University Hospital of Marburg, Marburg, Germany johannes.schumacher@uni-marburg.de.

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › GWAS meta-analysis of 16 790 patients with...
questionsmedicales.fr › Maladies de l'appareil digestif › Maladies gastro-intestinales › Maladies de l'oesophage › Oesophage de Barrett › GWAS meta-analysis of 16 790 patients with...
questionsmedicales.fr › Environnement et santé publique › Santé publique › Méthodes épidémiologiques › Épidémiologie moléculaire › Étude d'association pangénomique › GWAS meta-analysis of 16 790 patients with...
questionsmedicales.fr › Maladies de l'appareil digestif › Maladies gastro-intestinales › Tumeurs gastro-intestinales › Tumeurs de l'oesophage › GWAS meta-analysis of 16 790 patients with...
questionsmedicales.fr › Tumeurs › Tumeurs par type histologique › Tumeurs épithéliales épidermoïdes et glandulaires › Carcinomes › Adénocarcinome › GWAS meta-analysis of 16 790 patients with...