Andrew R Hamel, Wenjun Yan, John M Rouhana, Aboozar Monovarfeshani, Xinyi Jiang, Puja A Mehta, Jayshree Advani, Yuyang Luo, Qingnan Liang, Skanda Rajasundaram, Arushi Shrivastava, Katherine Duchinski, Sreekar Mantena, Jiali Wang, Tavé van Zyl, Louis R Pasquale, Anand Swaroop, Puya Gharahkhani, Anthony P Khawaja, Stuart MacGregor, International Glaucoma Genetics Consortium (IGGC), Rui Chen, Veronique Vitart, Joshua R Sanes, Janey L Wiggs, Ayellet V Segrè
Nature communications 2024 Jan 09Primary 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. © 2024. The Author(s).
Andrew R Hamel, Wenjun Yan, John M Rouhana, Aboozar Monovarfeshani, Xinyi Jiang, Puja A Mehta, Jayshree Advani, Yuyang Luo, Qingnan Liang, Skanda Rajasundaram, Arushi Shrivastava, Katherine Duchinski, Sreekar Mantena, Jiali Wang, Tavé van Zyl, Louis R Pasquale, Anand Swaroop, Puya Gharahkhani, Anthony P Khawaja, Stuart MacGregor, International Glaucoma Genetics Consortium (IGGC), Rui Chen, Veronique Vitart, Joshua R Sanes, Janey L Wiggs, Ayellet V Segrè. Integrating genetic regulation and single-cell expression with GWAS prioritizes causal genes and cell types for glaucoma. Nature communications. 2024 Jan 09;15(1):396
PMID: 38195602
View Full Text