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
Open Access
- 29 June 2021
- Vol. 71 (6), 1053-1061
- https://doi.org/10.1136/gutjnl-2020-323906
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
Funding Information
- National Health and Medical Research Council (1063061, 1123248)
This publication has 44 references indexed in Scilit:
- Role of Endoscopy in GERDGastroenterology Clinics of North America, 2014
- Surveillance of HCC Patients after Liver RFA: Role of MRI with Hepatospecific Contrast versus Three-Phase CT Scan—Experience of High Volume Oncologic InstituteGastroenterology Research and Practice, 2013
- Current Advances in the Diagnosis and Treatment of Nonerosive Reflux DiseaseGastroenterology Research and Practice, 2013
- The Genotype-Tissue Expression (GTEx) projectNature Genetics, 2013
- Host–microbe interactions have shaped the genetic architecture of inflammatory bowel diseaseNature, 2012
- Anxiety and depression in various functional gastrointestinal disorders: Do differences exist?Journal of Digestive Diseases, 2012
- Accuracy of the diagnosis of GORD by questionnaire, physicians and a trial of proton pump inhibitor treatment: the Diamond StudyGut, 2010
- The Effect of Auditory Stress on Perception of Intraesophageal Acid in Patients With Gastroesophageal Reflux DiseaseGastroenterology, 2008
- Exploring the neurophysiological basis of chest wall allodynia induced by experimental oesophageal acidification ? evidence of central sensitizationNeurogastroenterology & Motility, 2007
- Acid Perception in Gastro-oesophageal Reflux Disease is Dependent on Psychosocial FactorsScandinavian Journal of Gastroenterology, 1995