Genome-wide association study of epiretinal membrane in the Finnish population identifies novel associated genes that are expressed in patient-derived pathologic membranes

Abstract

Purpose : Epiretinal membrane (ERM) is a fibrocellular proliferation on the surface of the retina that occurs in 1-2% of the population and leads to significant vision loss. Aside from a handful of comorbidities known to be risk factors, the pathophysiology is poorly understood and there are currently no known genetic risk factors. The purpose of this study is to identify genetic risk loci for ERM and to use single cell expression data from patient-derived pathologic specimens to highlight critical genes.

Methods : We identified 2,995 cases and 341,547 controls in the FinnGen study. Cases were defined as patients with an ICD-10 code of H35.38. We applied a series of filters to cases and controls to remove all patients with any form of diabetic retinopathy, a disease that leads to a biologically different form of epiretinal membrane. We performed a genome-wide association study with sex, age at death or end of follow-up, first 10 PCs, genotyping array, and genotyping batch as covariates. For the loci that achieved genome-wide significance (5 x 10^-8), we investigated which genes therein were expressed uniformly in 5 patient-derived epiretinal membranes peeled during surgery for proliferative vitreoretinopathy at Mass Eye and Ear. We also queried expression quantitative trait loci in the Genotype-Tissue Expression (GTEx) project version 8.

Results : We identify six novel loci (p < 5 x 10^-8) for non-diabetic ERM. In the most significant locus, the lead variant (rs28630834 A>G) is intronic within DHX36 and is associated with increased DHX36 expression in cultured fibroblasts (p<8.7 x 10^-7) in GTEx. DHX36 (and not the other genes in the locus) is highly expressed in all surgical membrane specimens, suggesting that this gene plays an important role in primary ERM pathophysiology.

Conclusions : To our knowledge, this is one of the earliest reports of genetic associations for ERM in which we find 5 regions of the genome associated. Furthermore, DHX36 may play an important role in the pathophysiology of ERM given its expression in pathologic tissue specimens.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.

 

Figure 1. Manhattan plot for ERM GWAS.

 

Figure 2. Expression of DHX36 in PVR membranes. 7 membranes were analyzed for single-cell expression. CBM = ciliary body membrane; ERM = epiretinal membrane; PVR = proliferative vitreoretinopathy; SRM = subretinal membrane.