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Abstract #117718 Published in IGR 24-4
Integrating genetic regulation and single-cell expression with GWAS prioritizes causal genes and cell types for glaucoma
Hamel AR; Yan W; Rouhana JM; Monovarfeshani A; Jiang X; Mehta PA; Advani J; Luo Y; Liang Q; Rajasundaram S; Shrivastava A; Duchinski K; Mantena S; Wang J; van Zyl T; Pasquale LR; Swaroop A; Gharahkhani P; Khawaja AP; Macgregor S; ; Chen R; Vitart V; Sanes JR; Wiggs JL; Segrè AV; Segrè AVNature communications 2024; 15: 396
Primary open-angle glaucoma (POAG), characterized by retinal ganglion cell death, is a leading cause of irreversible blindness worldwide. However, its 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 overlapping expression and splicing quantitative trait loci (e/sQTLs) in 49 GTEx tissues and retina prioritizes causal genes for 60% of loci. These genes are enriched in pathways implicated in extracellular matrix organization, cell adhesion, and vascular development. Analysis of single-nucleus RNA-seq of glaucoma-relevant eye tissues reveals that the POAG and IOP colocalizing genes and genome-wide associations are enriched in specific cell types in the aqueous outflow pathways, retina, optic nerve head, peripapillary sclera, and choroid. This study nominates IOP-dependent and independent regulatory mechanisms, genes, and cell types that may contribute to POAG pathogenesis.
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