PT - JOURNAL ARTICLE AU - Julia Schröder AU - Laura Chegwidden AU - Carlo Maj AU - Jan Gehlen AU - Jan Speller AU - Anne C Böhmer AU - Oleg Borisov AU - Timo Hess AU - Nicole Kreuser AU - Marino Venerito AU - Hakan Alakus AU - Andrea May AU - Christian Gerges AU - Thomas Schmidt AU - Rene Thieme AU - Dominik Heider AU - Axel M Hillmer AU - Julian Reingruber AU - Orestis Lyros AU - Arne Dietrich AU - Albrecht Hoffmeister AU - Matthias Mehdorn AU - Florian Lordick AU - Gertraud Stocker AU - Michael Hohaus AU - Daniel Reim AU - Jennis Kandler AU - Michaela Müller AU - Alanna Ebigbo AU - Claudia Fuchs AU - Christiane J Bruns AU - Arnulf H Hölscher AU - Hauke Lang AU - Peter P Grimminger AU - Dani Dakkak AU - Yogesh Vashist AU - Sandra May AU - Siegfried Görg AU - Andre Franke AU - David Ellinghaus AU - Sara Galavotti AU - Lothar Veits AU - Josef Weismüller AU - Jens Dommermuth AU - Udo Benner AU - Thomas Rösch AU - Helmut Messmann AU - Brigitte Schumacher AU - Horst Neuhaus AU - Carsten Schmidt AU - Thaddäus T Wissinowski AU - Markus M Nöthen AU - Wellcome Trust Case Control Consortium 2 (WTCCC2) AU - Esophageal Adenocarcinoma Genetics Consortium (EAGLE) AU - Barrett's and Esophageal Adenocarcinoma Consortium (BEACON) AU - Jing Dong AU - Jue-Sheng Ong AU - Matthew F Buas AU - Aaron P Thrift AU - Thomas L Vaughan AU - Ian Tomlinson AU - David C Whiteman AU - Rebecca Claire Fitzgerald AU - Janusz Jankowski AU - Michael Vieth AU - Andreas Mayr AU - Puya Gharahkhani AU - Stuart MacGregor AU - Ines Gockel AU - Claire Palles AU - Johannes Schumacher TI - 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 AID - 10.1136/gutjnl-2021-326698 DP - 2023 Apr 01 TA - Gut PG - 612--623 VI - 72 IP - 4 4099 - http://gut.bmj.com/content/72/4/612.short 4100 - http://gut.bmj.com/content/72/4/612.full SO - Gut2023 Apr 01; 72 AB - 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.The dataset for BEACON is available in dbGAP and the dataset of the Cambridge cohort is available via EDAM (see supplement). The other datasets analysed during this study are not publicly available due to non-conformity with consent forms but are available from the corresponding author on reasonable request.