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

Schröder J, Chegwidden L, Maj C, Gehlen J, Speller J, Böhmer AC, Borisov O, Hess T, Kreuser N, Venerito M, Alakus H, May A, Gerges C, Schmidt T, Thieme R, Heider D, Hillmer AM, Reingruber J, Lyros O, Dietrich A, Hoffmeister A, Mehdorn M, Lordick F, Stocker G, Hohaus M, Reim D, Kandler J, Müller M, Ebigbo A, Fuchs C, Bruns CJ, Hölscher AH, Lang H, Grimminger PP, Dakkak D, Vashist Y, May S, Görg S, Franke A, Ellinghaus D, Galavotti S, Veits L, Weismüller J, Dommermuth J, Benner U, Rösch T, Messmann H, Schumacher B, Neuhaus H, Schmidt C, Wissinowski TT, Nöthen MM, Dong J, Ong JS, Buas MF, Thrift AP, Vaughan TL, Tomlinson I, Whiteman DC, Fitzgerald RC, Jankowski J, Vieth M, Mayr A, Gharahkhani P, MacGregor S, Gockel I, Palles C, Schumacher J (2022)

Publication Language: English

Publication Type: Journal article

Publication year: 2022

Journal

Book Volume: 72

Pages Range: 612-623

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.

Authors with CRIS profile

Involved external institutions

Johannes Gutenberg-Universität Mainz (JGU) Germany (DE) Elisabeth-Krankenhaus Essen Germany (DE) Christian-Albrechts-Universität zu Kiel Germany (DE) University of Birmingham United Kingdom (GB) Klinikum Chemnitz Germany (DE) QIMR Berghofer Medical Research Institute (früher: the Queensland Institute of Medical Research) Australia (AU) Universitätsklinikum Leipzig Germany (DE) Evangelisches Krankenhaus Düsseldorf Germany (DE) Universitätsklinikum Köln Germany (DE) Philipps-Universität Marburg Germany (DE) Universität Leipzig Germany (DE) Technische Universität München (TUM) Germany (DE) Universitätsklinikum Gießen und Marburg (UKGM) Germany (DE) Universitätsklinikum Augsburg Germany (DE) Rheinische Friedrich-Wilhelms-Universität Bonn Germany (DE) Medical College of Wisconsin (MCW) United States (USA) (US) Fred Hutchinson Cancer Research Center United States (USA) (US) University of Cambridge United Kingdom (GB) University College London (UCL) United Kingdom (GB) Roswell Park Cancer Institute United States (USA) (US) Houston Texas Medical Center United States (USA) (US) Universitätsklinikum Hamburg-Eppendorf (UKE) Germany (DE) University of Edinburgh United Kingdom (GB) Otto-von-Guericke-Universität Magdeburg Germany (DE) Asklepios Klinik Wiesbaden Germany (DE) Krankenhaus Dresden-Friedrichstadt, Städtisches Klinikum Germany (DE) Heinrich-Heine-Universität Düsseldorf Germany (DE) Medias Klinikum Germany (DE) Universitätsklinikum Schleswig-Holstein (UKSH) Germany (DE)

How to cite

APA:

Schröder, J., Chegwidden, L., Maj, C., Gehlen, J., Speller, J., Böhmer, A.C.,... Schumacher, J. (2022). 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. Gut, 72, 612-623. https://doi.org/10.1136/gutjnl-2021-326698

MLA:

Schröder, Julia, et al. "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." Gut 72 (2022): 612-623.

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