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

Journal article

Primary 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 and Mendelian randomization analysis of >240 POAG and IOP genome-wide association study (GWAS) loci and of overlapping expression and splicing quantitative trait loci (e/QTLs and sQTLs) in 49 GTEx tissues and retina prioritizesd causal genes for 60% of loci. These genes awere enriched in pathways implicated in extracellular matrix organization, cell adhesion, and vascular development. Analysis of single-nucleus RNA-seq of glaucoma-relevant eye tissues revealesd that the colocalizing genes and genome-wide POAG and IOP associations awere enriched in specific cell types in the aqueous outflow pathways, retina, optic nerve head, peripapillary sclera, and choroid. This study nominatesd IOP-dependent and independent regulatory mechanisms, genes, and cell types that may contribute to POAG pathogenesis

Authors: Hamel, AR; Yan, W; Rouhana, JM; Monovarfeshani, A; Jiang, X

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Nature Research
• Journal: Nature Communications
• Volume: 15
• Issue: 1
• Pages: 396-396
• Article number: 396
• Publication date: 2024-01-09
• DOI: 10.1038/s41467-023-44380-y
• EISSN: 2041-1723
• ISSN: 2041-1723
• Language: English
• Keywords: Genome-wide association study; Biology; Computational biology; Genotype; Single-nucleotide polymorphism; Gene expression; Cell; Genetics; Bioinformatics; Gene