Integrating genetic regulation and single-cell expression with GWAS prioritizes causal genes and cell types for glaucoma

Abstract

AbstractPrimary open-angle glaucoma (POAG), characterized by retinal ganglion cell death, is a leading cause of irreversible blindness worldwide; however the molecular and cellular causes are not well understood. Elevated intraocular pressure (IOP) is a major risk factor, but many patients have normal IOP. Colocalization analysis of >130 POAG and 112 IOP GWAS loci and overlapping expression and splicing quantitative trait loci (e/sQTLs) in 49 GTEx tissues and retina proposed causal genes for 60% of the loci, that were enriched in extracellular matrix organization, cell adhesion, and vascular development. Analyzing single-nucleus RNA-seq of glaucoma-relevant eye tissues, we found that the colocalizing genes were enriched in known and less well-characterized cell types, including fibroblasts in the conventional and unconventional aqueous outflow pathways; vascular cells in the anterior segment; astrocytes and Müller glia in retina and optic nerve head (ONH); and smooth muscle and vascular endothelial cells in ONH. This study nominated IOP- dependent and independent regulatory mechanisms, genes, and cell types that may underlie POAG pathogenesis.