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

Abstract

IMPORTANCEEpiretinal 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. OBJECTIVEGenomewide association studies (GWAS) can reveal the biology underlying complex genetic traits like ERM; there have been no previous large-scale GWAS of this trait. DESIGNWe 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. SETTINGVeterans who volunteered for the nationwide Department of Veterans Affairs MVP study, eligible because they have used Veterans Health Administration facilities PARTICIPANTS31,374 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. METHODSWe 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 MEASURESGenomewide-significant association with ERM. RESULTSGenomewide 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 RELEVANCEThis well-powered ERM GWAS has identified novel genetic associations, some very strong, that point to biological mechanisms for ERM and merit further investigation.