Multitrait genetic association analysis identifies 50 new risk loci for gastro-oesophageal reflux, seven new loci for Barrett's oesophagus and provides insights into clinical heterogeneity in reflux diagnosis

Jue-Sheng Ong; Jiyuan An; Xikun Han; Matthew H Law; Priyanka Nandakumar; 23andMe Research team; Esophageal cancer consortium; Johannes Schumacher; Ines Gockel; Anne Bohmer; Janusz Jankowski; Claire Palles; Catherine M Olsen; Rachel E Neale; Rebecca Fitzgerald; Aaron P Thrift; Thomas L Vaughan; Matthew F Buas; David A Hinds; Puya Gharahkhani; Bradley J Kendall; Stuart MacGregor

doi:10.1136/gutjnl-2020-323906

Multitrait genetic association analysis identifies 50 new risk loci for gastro-oesophageal reflux, seven new loci for Barrett's oesophagus and provides insights into clinical heterogeneity in reflux diagnosis

Gut. 2022 Jun;71(6):1053-1061. doi: 10.1136/gutjnl-2020-323906. Epub 2021 Jun 29.

Authors

Jue-Sheng Ong¹, Jiyuan An², Xikun Han³, Matthew H Law^{3

4}, Priyanka Nandakumar⁵; 23andMe Research team; Esophageal cancer consortium; Johannes Schumacher⁶, Ines Gockel⁷, Anne Bohmer⁸, Janusz Jankowski^{9

10}, Claire Palles¹¹, Catherine M Olsen^{12

13}, Rachel E Neale¹², Rebecca Fitzgerald¹⁴, Aaron P Thrift¹⁵, Thomas L Vaughan¹⁶, Matthew F Buas¹⁷, David A Hinds⁵, Puya Gharahkhani³, Bradley J Kendall^{13

18}, Stuart MacGregor³

Collaborators

Rebecca Fitzgerald, Matt Buas, Marilie D Gammon, Douglas A Corley, Nicholas J Shaheen, Laura J Hardie, Nigel C Bird, Brian J Reid, Wong-Ho Chow, Harvey A Risch, Weimin Ye, Geoffrey Liu, Yvonne Romero, Leslie Bernstein, Anna H Wu, Johannes Schumacher, Ines Gockel, Anne Bohmer, Janusz Jankowski, Claire Palles, David C Whiteman, Michelle Agee, Stella Aslibekyan, Adam Auton, Robert K Bell, Katarzyna Bryc, Sarah K Clark, Sarah L Elson, Kipper Fletez-Brant, Pierre Fontanillas, Nicholas A Furlotte, Pooja M Gandhi, Karl Heilbron, Barry Hicks, David A Hinds, Karen E Huber, Ethan M Jewett, Yunxuan Jiang, Aaron Kleinman, Keng-Han Lin, Nadia K Litterman, Marie K Luff, Jennifer C McCreight, Matthew H McIntyre, Kimberly F McManus, Joanna L Mountain, Sahar V Mozaffari, Priyanka Nandakumar, Elizabeth S Noblin, Carrie Am Northover, Jared O'Connell, Aaron A Petrakovitz, Steven J Pitts, G David Poznik, J Fah Sathirapongsasuti, Anjali J Shastri, Janie F Shelton, Suyash Shringarpure, Chao Tian, Joyce Y Tung, Robert J Tunney, Vladimir Vacic, Xin Wang, Amir S Zare

Affiliations

¹ Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia juesheng.ong@qimrberghofer.edu.au.
² School of Biology & Environmental Science, Queensland University of Technology, Brisbane, Queensland, Australia.
³ Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.
⁴ Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Queensland, Australia.
⁵ 23andMe, Mountain View, California, USA.
⁶ Institute of Human Genetics, Philipps University of Marburg, Marburg, Germany.
⁷ Department of Visceral, Transplant, Thoracic and Vascular Surgery, University Hospital Leipzig, Leipzig, Germany.
⁸ Institute of Human Genetics, University of Bonn, Bonn, Germany.
⁹ Centre for Medicine and Health Sciences, University of United Arab Emirates, Al Ain, Abu Dhabi, UAE.
¹⁰ UCL Medical School, University College London, London, UK.
¹¹ Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK.
¹² Department of Population Health, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.
¹³ Faculty of Medicine, The University of Queensland, Herston, Queensland, Australia.
¹⁴ MRC Cancer Center, University of Cambridge, Cambridge, UK.
¹⁵ Department of Medicine, and Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, Texas, USA.
¹⁶ Department of Epidemiology, University of Washington School of Public Health, Seattle, Washington, USA.
¹⁷ Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA.
¹⁸ Department of Gastroenterology and Hepatology, Princess Alexandra Hospital, Woolloongabba, Queensland, Australia.

Abstract

Objective: Gastro-oesophageal reflux disease (GERD) has heterogeneous aetiology primarily attributable to its symptom-based definitions. GERD genome-wide association studies (GWASs) have shown strong genetic overlaps with established risk factors such as obesity and depression. We hypothesised that the shared genetic architecture between GERD and these risk factors can be leveraged to (1) identify new GERD and Barrett's oesophagus (BE) risk loci and (2) explore potentially heterogeneous pathways leading to GERD and oesophageal complications.

Design: We applied multitrait GWAS models combining GERD (78 707 cases; 288 734 controls) and genetically correlated traits including education attainment, depression and body mass index. We also used multitrait analysis to identify BE risk loci. Top hits were replicated in 23andMe (462 753 GERD cases, 24 099 BE cases, 1 484 025 controls). We additionally dissected the GERD loci into obesity-driven and depression-driven subgroups. These subgroups were investigated to determine how they relate to tissue-specific gene expression and to risk of serious oesophageal disease (BE and/or oesophageal adenocarcinoma, EA).

Results: We identified 88 loci associated with GERD, with 59 replicating in 23andMe after multiple testing corrections. Our BE analysis identified seven novel loci. Additionally we showed that only the obesity-driven GERD loci (but not the depression-driven loci) were associated with genes enriched in oesophageal tissues and successfully predicted BE/EA.

Conclusion: Our multitrait model identified many novel risk loci for GERD and BE. We present strong evidence for a genetic underpinning of disease heterogeneity in GERD and show that GERD loci associated with depressive symptoms are not strong predictors of BE/EA relative to obesity-driven GERD loci.

Keywords: Barrett's oesophagus; gastro-esophageal reflux disease; genetics; oesophageal reflux.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Barrett Esophagus* / complications
Barrett Esophagus* / diagnosis
Barrett Esophagus* / genetics
Esophageal Neoplasms* / diagnosis
Esophageal Neoplasms* / genetics
Esophagitis, Peptic*
Gastroesophageal Reflux* / complications
Gastroesophageal Reflux* / diagnosis
Gastroesophageal Reflux* / genetics
Genome-Wide Association Study
Humans
Obesity / complications
Obesity / genetics

Abstract

Publication types

MeSH terms

Grants and funding