{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,25]],"date-time":"2026-07-25T05:47:30Z","timestamp":1784958450056,"version":"3.55.0"},"reference-count":34,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2022,11,2]],"date-time":"2022-11-02T00:00:00Z","timestamp":1667347200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["92163213"],"award-info":[{"award-number":["92163213"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81970085"],"award-info":[{"award-number":["81970085"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["92163213"],"award-info":[{"award-number":["92163213"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81970085"],"award-info":[{"award-number":["81970085"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Background: Observational research has found a bidirectional relationship between major depressive disorder and gastroesophageal reflux disease; however, the causal association of this relationship is undetermined. Aims: A bidirectional Mendelian randomization study was performed to explore the causal relationships between major depressive disorder and gastroesophageal reflux disease. Methods: For the instrumental variables of major depressive disorder and gastroesophageal reflux disease, 31 and 24 single-nucleotide polymorphisms without linkage disequilibrium (r2 \u2264 0.001) were selected from relevant genome-wide association studies, respectively, at the genome-wide significance level (p \u2264 5 \u00d7 10\u22128). We sorted summary-level genetic data for major depressive disorder, gastroesophageal reflux disease, gastroesophageal reflux disease without esophagitis, and reflux esophagitis from meta-analysis study of genome-wide association studies involving 173,005 individuals (59,851 cases and 113,154 non-cases), 385,276 individuals (80,265 cases and 305,011 non-cases), 463,010 individuals (4360 cases and 458,650 non-cases), and 383,916 individuals (12,567 cases and 371,349 non-cases), respectively. Results: Genetic liability to major depressive disorder was positively associated with gastroesophageal reflux disease and its subtypes. Per one-unit increase in log-transformed odds ratio of major depressive disorder, the odds ratio was 1.31 (95% confidence interval [CI], 1.19\u20131.43; p = 1.64 \u00d7 10\u22128) for gastroesophageal reflux disease, 1.51 (95% CI, 1.15\u20131.98; p = 0.003) for gastroesophageal reflux disease without esophagitis, and 1.21 (95% CI, 1.05\u20131.40; p = 0.010) for reflux esophagitis. Reverse-direction analysis suggested that genetic liability to gastroesophageal reflux disease was causally related to increasing risk of major depressive disorder. Per one-unit increase in log-transformed odds ratio of gastroesophageal reflux disease, the odds ratio of major depressive disorder was 1.28 (95% confidence interval, 1.11\u20131.47; p = 1.0 \u00d7 10\u22123). Conclusions: This Mendelian randomization study suggests a bidirectional causal relationship between major depressive disorder and gastroesophageal reflux disease.<\/jats:p>","DOI":"10.3390\/genes13112010","type":"journal-article","created":{"date-parts":[[2022,11,3]],"date-time":"2022-11-03T03:11:21Z","timestamp":1667445081000},"page":"2010","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Bidirectional Association between Major Depressive Disorder and Gastroesophageal Reflux Disease: Mendelian Randomization Study"],"prefix":"10.3390","volume":"13","author":[{"given":"Yuyang","family":"Miao","sequence":"first","affiliation":[{"name":"Department of Geriatrics, Tianjin Medical University General Hospital, Tianjin 300052, China"},{"name":"Tianjin Geriatrics Institute, Tianjin 300052, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5055-5627","authenticated-orcid":false,"given":"Shuai","family":"Yuan","sequence":"additional","affiliation":[{"name":"Unit of Cardiovascular and Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, 17177 Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2236-9728","authenticated-orcid":false,"given":"Ye","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Geriatrics, Tianjin Medical University General Hospital, Tianjin 300052, China"},{"name":"Tianjin Geriatrics Institute, Tianjin 300052, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4029-4192","authenticated-orcid":false,"given":"Jie","family":"Chen","sequence":"additional","affiliation":[{"name":"Centre for Global Health, Zhejiang University School of Medicine, Hangzhou 310030, China"},{"name":"Department of Gastroenterology, The Third Xiangya Hospital, Central South University, Changsha 410017, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xue","family":"Li","sequence":"additional","affiliation":[{"name":"School of Public Health and the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310030, China"},{"name":"Centre for Global Health, Usher Institute, The University of Edinburgh, Edinburgh EH8 9YL, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0118-0341","authenticated-orcid":false,"given":"Susanna C.","family":"Larsson","sequence":"additional","affiliation":[{"name":"Unit of Cardiovascular and Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, 17177 Stockholm, Sweden"},{"name":"Unit of Medical Epidemiology, Department of Surgical Sciences, Uppsala University, 75236 Uppsala, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiang","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Geriatrics, Tianjin Medical University General Hospital, Tianjin 300052, China"},{"name":"Tianjin Geriatrics Institute, Tianjin 300052, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,11,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"16065","DOI":"10.1038\/nrdp.2016.65","article-title":"Major depressive disorder","volume":"2","author":"Otte","year":"2016","journal-title":"Nat. Rev. Dis. Prim."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1789","DOI":"10.1016\/S0140-6736(18)32279-7","article-title":"Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990\u20132017: A systematic analysis for the Global Burden of Disease Study 2017","volume":"392","author":"James","year":"2018","journal-title":"Lancet"},{"key":"ref_3","first-page":"168","article-title":"Lifetime prevalence and age-of-onset distributions of mental disorders in the World Health Organization\u2019s World Mental Health Survey Initiative","volume":"6","author":"Kessler","year":"2007","journal-title":"World Psychiatry"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1038\/s41572-021-00287-w","article-title":"Gastro-oesophageal reflux disease","volume":"7","author":"Fass","year":"2021","journal-title":"Nat. Rev. Dis. Prim."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1001\/jamasurg.2015.4233","article-title":"An Evidence-Based Approach to the Treatment of Gastroesophageal Reflux Disease","volume":"151","author":"Patti","year":"2016","journal-title":"JAMA Surg."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1907","DOI":"10.1046\/j.1365-2036.2001.01131.x","article-title":"Reflux symptoms are associated with psychiatric disease","volume":"15","author":"Avidan","year":"2001","journal-title":"Aliment. Pharmacol. Ther."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1132","DOI":"10.1111\/j.1365-2036.2010.04280.x","article-title":"Depression and treatment with antidepressants are associated with the development of gastro-oesophageal reflux disease","volume":"31","author":"Wallander","year":"2010","journal-title":"Aliment. Pharmacol. Ther."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"534","DOI":"10.1016\/j.ejim.2015.05.005","article-title":"Risk of psychiatric disorders following gastroesophageal reflux disease: A nationwide population-based cohort study","volume":"26","author":"You","year":"2015","journal-title":"Eur. J. Intern. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1111\/j.1365-2036.2008.03883.x","article-title":"Review article: Gastro-oesophageal reflux disease and psychological comorbidity","volume":"29","author":"Mizyed","year":"2009","journal-title":"Aliment. Pharmacol. Ther."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"186","DOI":"10.12688\/wellcomeopenres.15555.1","article-title":"Guidelines for performing Mendelian randomization investigations","volume":"4","author":"Burgess","year":"2019","journal-title":"Wellcome Open Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2333","DOI":"10.1177\/0962280215597579","article-title":"A review of instrumental variable estimators for Mendelian randomization","volume":"26","author":"Burgess","year":"2017","journal-title":"Stat. Methods Med. Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"668","DOI":"10.1038\/s41588-018-0090-3","article-title":"Genome-wide association analyses identify 44 risk variants and refine the genetic architecture of major depression","volume":"50","author":"Wray","year":"2018","journal-title":"Nat. Genet."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"4219","DOI":"10.1038\/s41467-019-11968-2","article-title":"Gastroesophageal reflux GWAS identifies risk loci that also associate with subsequent severe esophageal diseases","volume":"10","author":"An","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"658","DOI":"10.1002\/gepi.21758","article-title":"Mendelian randomization analysis with multiple genetic variants using summarized data","volume":"37","author":"Burgess","year":"2013","journal-title":"Genet. Epidemiol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"304","DOI":"10.1002\/gepi.21965","article-title":"Consistent Estimation in Mendelian Randomization with Some Invalid Instruments Using a Weighted Median Estimator","volume":"40","author":"Bowden","year":"2016","journal-title":"Genet. Epidemiol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1093\/ije\/dyv080","article-title":"Mendelian randomization with invalid instruments: Effect estimation and bias detection through Egger regression","volume":"44","author":"Bowden","year":"2015","journal-title":"Int. J. Epidemiol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1038\/s41588-018-0099-7","article-title":"Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases","volume":"50","author":"Verbanck","year":"2018","journal-title":"Nat. Genet."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"376","DOI":"10.1038\/s41467-019-14156-4","article-title":"A robust and efficient method for Mendelian randomization with hundreds of genetic variants","volume":"11","author":"Burgess","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1497","DOI":"10.1093\/ije\/dyt179","article-title":"Calculating statistical power in Mendelian randomization studies","volume":"42","author":"Brion","year":"2013","journal-title":"Int. J. Epidemiol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"e34408","DOI":"10.7554\/eLife.34408","article-title":"The MR-Base platform supports systematic causal inference across the human phenome","volume":"7","author":"Hemani","year":"2018","journal-title":"eLife"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1734","DOI":"10.1093\/ije\/dyx034","article-title":"MendelianRandomization: An R package for performing Mendelian randomization analyses using summarized data","volume":"46","author":"Yavorska","year":"2017","journal-title":"Int. J. Epidemiol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1016\/j.psym.2013.06.003","article-title":"Prevalence of gastroesophageal reflux disease in major depressive disorder: A population-based study","volume":"55","author":"Chou","year":"2014","journal-title":"Psychosomatics"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1170","DOI":"10.1111\/jgh.13650","article-title":"The association between gastroesophageal reflux disease with sleep quality, depression, and anxiety in a cohort study of Australian men","volume":"32","author":"On","year":"2017","journal-title":"J. Gastroenterol. Hepatol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"683","DOI":"10.1111\/j.1365-2036.2007.03411.x","article-title":"Severe gastro-oesophageal reflux symptoms in relation to anxiety, depression and coping in a population-based study","volume":"26","author":"Jansson","year":"2007","journal-title":"Aliment. Pharmacol. Ther."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"11748","DOI":"10.1038\/s41598-018-29629-7","article-title":"Bidirectional association between gastroesophageal reflux disease and depression: Two different nested case-control studies using a national sample cohort","volume":"8","author":"Kim","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"6523","DOI":"10.3748\/wjg.v19.i39.6523","article-title":"Gastroesophageal reflux disease: Update on inflammation and symptom perception","volume":"19","author":"Altomare","year":"2013","journal-title":"World J. Gastroenterol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1776","DOI":"10.1053\/j.gastro.2009.07.055","article-title":"Gastroesophageal reflux might cause esophagitis through a cytokine-mediated mechanism rather than caustic acid injury","volume":"137","author":"Souza","year":"2009","journal-title":"Gastroenterology"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1111\/imm.12443","article-title":"Immune mechanisms linked to depression via oxidative stress and neuroprogression","volume":"144","author":"Bakunina","year":"2015","journal-title":"Immunology"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1038\/mp.2013.35","article-title":"Long-term inflammation increases risk of common mental disorder: A cohort study","volume":"19","author":"Shipley","year":"2014","journal-title":"Mol. Psychiatry"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"12728","DOI":"10.1073\/pnas.1118748109","article-title":"Peripheral inflammatory disease associated with centrally activated IL-1 system in humans and mice","volume":"109","author":"Lampa","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"815","DOI":"10.1007\/s00535-004-1416-8","article-title":"The relationship between gastroesophageal reflux disease and obstructive sleep apnea","volume":"39","author":"Demeter","year":"2004","journal-title":"J. Gastroenterol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"960","DOI":"10.1016\/j.cgh.2009.03.007","article-title":"A population-based study showing an association between gastroesophageal reflux disease and sleep problems","volume":"7","author":"Jansson","year":"2009","journal-title":"Clin. Gastroenterol. Hepatol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1046\/j.1442-2050.2002.00261.x","article-title":"Psychological and emotional aspects of gastroesophageal reflux disease","volume":"15","author":"Kamolz","year":"2002","journal-title":"Dis. Esophagus"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"274","DOI":"10.4140\/TCP.n.2011.274","article-title":"Antidepressant-mediated gastroesophageal reflux disease","volume":"26","author":"Brahm","year":"2011","journal-title":"Consult. Pharm."}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/13\/11\/2010\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:09:22Z","timestamp":1760144962000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/13\/11\/2010"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,11,2]]},"references-count":34,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2022,11]]}},"alternative-id":["genes13112010"],"URL":"https:\/\/doi.org\/10.3390\/genes13112010","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,11,2]]}}}