Genomewide association study of epiretinal membrane: discovery of significant risk loci in each of three American populations

IMPORTANCE: Epiretinal membrane (ERM) is a common retinal condition characterized by the presence of fibrocellular tissue on the retinal surface, often with consequent loss of vision and visual distortion. OBJECTIVE: Genomewide association studies (GWAS) can reveal the biology underlying complex genetic traits like ERM; there have been no previous large-scale GWAS of this trait. DESIGN: We used electronic health record diagnosis to identify Million Veteran Program (MVP) participants with ERM in three populations for genomewide association analysis and further statistical investigation of the results. SETTING: Veterans who volunteered for the nationwide Department of Veterans Affairs MVP study, eligible because they have used Veterans Health Administration facilities PARTICIPANTS: 31,374 European-American (EUR) cases and 414,052 EUR controls, 4,739 African-American (AFR) cases and 107,773 AFR controls, and 2,119 Latino (Admixed American, AMR) cases and 36,163 AMR controls, a total of 38,232 cases and 557,988 controls. METHODS: We completed GWAS in each population separately, then results were meta-analyzed. We also evaluated genetic correlation with other traits in external samples, and completed pathway enrichment analyses. MAIN OUTCOME MEASURES: Genomewide-significant association with ERM. RESULTS: Genomewide significant associations were observed in all three populations studied: 31 risk loci in EUR subjects, 3 in AFR, and 2 in AMR, with 48 identified in trans-ancestry meta-analysis. The most strongly associated locus in both EUR (rs9823832, p=9.06x10-37) and the meta-analysis (rs28630834, p=2.90x10-37) was DHX36 (DEAH-Box Helicase 36). We investigated expression quantitative trait locus associations for eye related function and found several GWS variants associate to alterations in gene expression in the macula, including DHX36*rs9438. ERM showed significant genetic correlation to depression and to disorders of the vitreous. Pathway enrichment analyses implicated collagen and collagen-adjacent mechanisms, among others. CONCLUSIONS AND RELEVANCE: This well-powered ERM GWAS has identified novel genetic associations, some very strong, that point to biological mechanisms for ERM and merit further investigation. ### Competing Interest Statement Dr. Gelernter is named as an inventor on PCT patent application #15/878,640 entitled: Genotype-guided dosing of opioid agonists, filed January 24, 2018 and issued on January 26, 2021 as U.S. Patent No. 10,900,082. Dr. Gelernter is paid for editorial work for the journal Complex Psychiatry (Karger). Dr. Eliot is ad hoc consultant for Alcon, Dutch Ophthalmic, GelMEDIX, and Genentech; reports research funding from Neurotech and Unity Biotechnology; is a member of the Advisory Board & Stockholder for InGel Therapeutics, Pykus Therapeutics, and RetMap; reports being Advisor, Patents, Royalties, and Stockholder in Aldeyra Therapeutics; and is a member of the Data Safety Monitoring Board (DSMB) for Asclepix Dr. Stein has in the past 3 years received consulting income from Acadia Pharmaceuticals, Aptinyx, atai Life Sciences, BigHealth, Bionomics, BioXcel Therapeutics, Boehringer Ingelheim, Clexio, Eisai, EmpowerPharm, Engrail Therapeutics, Janssen, Jazz Pharmaceuticals, NeuroTrauma Sciences, PureTech Health, Sumitomo Pharma, and Roche/Genentech. Dr. Stein has stock options in Oxeia Biopharmaceuticals and EpiVario. He has been paid for his editorial work on Depression and Anxiety (Editor-in-Chief), Biological Psychiatry (Deputy Editor), and UpToDate (Co-Editor-in-Chief for Psychiatry). He is on the scientific advisory board for the Brain and Behavior Research Foundation and the Anxiety and Depression Association of America. ### Funding Statement This research is based on data from the Million Veteran Program (MVP), Office of Research and Development, Veterans Health Administration, and was supported by the MVP and the Veterans Affairs Cooperative Studies Program study No. 575B. This work was also supported funding from the Department of Veterans Affairs Office of Research and Development grants I01CX001849, MVP025. D.F.L. was supported by a was supported by an NARSAD Young Investigator Grant from the Brain & Behavior Research Foundation and a Career Development Award CDA-2 from the Veterans Affairs Office of Research and Development (1IK2BX005058-01A2) and is Aimee Mann Fellow of Psychiatric Genetics. This publication does not represent the views of the Department of Veterans Affairs or the United States Government. We also acknowledge the participants and investigators of the FinnGen study. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Veterans Affairs Central IRB committee Panel 2 approved this research, project MVP025 19-02. This project was also approved by VA local IRBs in Boston MA, San Diego CA, and West Haven CT. The Million Veteran Program Publication Committee approved this research and publication. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data will be made available through dbGAP upon publication of the article. https://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs001672.v9.p1