@article {Schr{\"o}der612, author = {Julia Schr{\"o}der and Laura Chegwidden and Carlo Maj and Jan Gehlen and Jan Speller and Anne C B{\"o}hmer and Oleg Borisov and Timo Hess and Nicole Kreuser and Marino Venerito and Hakan Alakus and Andrea May and Christian Gerges and Thomas Schmidt and Rene Thieme and Dominik Heider and Axel M Hillmer and Julian Reingruber and Orestis Lyros and Arne Dietrich and Albrecht Hoffmeister and Matthias Mehdorn and Florian Lordick and Gertraud Stocker and Michael Hohaus and Daniel Reim and Jennis Kandler and Michaela M{\"u}ller and Alanna Ebigbo and Claudia Fuchs and Christiane J Bruns and Arnulf H H{\"o}lscher and Hauke Lang and Peter P Grimminger and Dani Dakkak and Yogesh Vashist and Sandra May and Siegfried G{\"o}rg and Andre Franke and David Ellinghaus and Sara Galavotti and Lothar Veits and Josef Weism{\"u}ller and Jens Dommermuth and Udo Benner and Thomas R{\"o}sch and Helmut Messmann and Brigitte Schumacher and Horst Neuhaus and Carsten Schmidt and Thadd{\"a}us T Wissinowski and Markus M N{\"o}then and Wellcome Trust Case Control Consortium 2 (WTCCC2) and Esophageal Adenocarcinoma Genetics Consortium (EAGLE) and Barrett{\textquoteright}s and Esophageal Adenocarcinoma Consortium (BEACON) and Jing Dong and Jue-Sheng Ong and Matthew F Buas and Aaron P Thrift and Thomas L Vaughan and Ian Tomlinson and David C Whiteman and Rebecca Claire Fitzgerald and Janusz Jankowski and Michael Vieth and Andreas Mayr and Puya Gharahkhani and Stuart MacGregor and Ines Gockel and Claire Palles and Johannes Schumacher}, editor = {, and Donnelly, Peter and Barroso, Ines and Blackwell, Jenefer M and Bramon, Elvira and Brown, Matthew A and Casas, Juan P and Corvin, Aiden and Deloukas, Panos and Duncanson, Audrey and Jankowski, Janusz and Markus, Hugh S and Mathew, Christopher G and Palmer, Colin NA and Plomin, Robert and Rautanen, Anna and Sawcer, Stephen J and Trembath, Richard C and Viswanathan, Ananth C and Wood, Nicholas W and Spencer, Chris C A and Band, Gavin and Bellenguez, C{\'e}line and Freeman, Colin and Hellenthal, Garrett and Giannoulatou, Eleni and Pirinen, Matti and Pearson, Richard and Strange, Amy and Su, Zhan and Vukcevic, Damjan and Donnelly, Peter and Langford, Cordelia and Hunt, Sarah E and Edkins, Sarah and Gwilliam, Rhian and Blackburn, Hannah and Bumpstead, Suzannah J and Dronov, Serge and Gillman, Matthew and Gray, Emma and Hammond, Naomi and Jayakumar, Alagurevathi and McCann, Owen T and Liddle, Jennifer and Potter, Simon C and Ravindrarajah, Radhi and Ricketts, Michelle and Waller, Matthew and Weston, Paul and Widaa, Sara and Whittaker, Pamela and Barroso, Ines and Deloukas, Panos and Mathew, Christopher G and Blackwell, Jenefer M and Brown, Matthew A and Corvin, Aiden and Spencer, Chris CA and , and Isaacs, Peter and Beckett, Conrad and Cullen, Sue and Hobday, David and Dhar, Ameet and Kejariwal, Deepak and Shutt, James and Sargeant, Ian and Koss, Konrad and Grimley, Charles and Barr, Hugh and Winter, Helen and Dixon, Andrew and McMurty, Hugh and Johnson, Matthew and Ali, Haythem and Lazon-Miller, Sandro and Paterson, Stuart and Beales, Ian and MacDonald, Chris and Rutter, Matt and Moran, Alex and Haig, Chris and Ragunath, Krish and Senapati, Siba and Bhandari, Pradeep and Wajed, Saj and Alam, Salma and Farrent, Mark and Ang, Yeng and Trudgill, Nigel and Smith, Mark and George, Keith and Ramadas, Arvind and Panter, Simon and Patel, Vinod and Lovat, Laurence and Kelly, Mark and Patel, Praful and Falk, Stephen and Nwokolo, Chuka and deCaestecker, John and Ramakrishnan, Subramaniam and Eng, Yang and Kelly, Sean and Tucker, Art and Mullins, Paul and Prenen, Hans and Jankowski, Janusz and , and Gammon, Marilie D and Corley, Douglas A and Shaheen, Nicholas J and Bird, Nigel C and Hardie, Laura J and Murray, Liam J and Reid, Brian J and Chow, Wong-Ho and Risch, Harvey A and Ye, Weimin and Liu, Geoffrey and Bernstein, Leslie and Iyer, Prasad and Anderson, Lesley and Lagergren, Jesper and Fitzgerald, Rebecca and Wu, Anna H and Whiteman, David C and Vaughan, Thomas L}, title = {GWAS meta-analysis of 16 790 patients with Barrett{\textquoteright}s oesophagus and oesophageal adenocarcinoma identifies 16 novel genetic risk loci and provides insights into disease aetiology beyond the single marker level}, volume = {72}, number = {4}, pages = {612--623}, year = {2023}, doi = {10.1136/gutjnl-2021-326698}, publisher = {BMJ Publishing Group}, abstract = {Objective Oesophageal cancer (EC) is the sixth leading cause of cancer-related deaths. Oesophageal adenocarcinoma (EA), with Barrett{\textquoteright}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.}, issn = {0017-5749}, URL = {https://gut.bmj.com/content/72/4/612}, eprint = {https://gut.bmj.com/content/72/4/612.full.pdf}, journal = {Gut} }