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

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.

Author(s): Andrew R. Hamel 1,2,3, Wenjun Yan 4,62, John M. Rouhana1,2,3,62, Aboozar Monovarfeshani4,62, Xinyi Jiang 5,6, Puja A. Mehta 1,2,3, Jayshree Advani7, Yuyang Luo1,2,3, Qingnan Liang 8, SkandaRajasundaram2,9,10, Arushi Shrivastava 1,2,3, Katherine Duchinski 1,2,3,11, Sreekar Mantena 1,12, Jiali Wang 1,2,3, Tavévan Zyl4,13, Louis R. Pasquale14, Anand Swaroop 7, Puya Gharahkhani 15, Anthony P. Khawaja 16, Stuart MacGregor 15, International Glaucoma Genetics Consortium (IGGC), Rui Chen 8, Veronique Vitart 5, Joshua R. Sanes 4, Janey L. Wiggs 1,2,3 & Ayellet V. Segrè

Experimental Paper of the Month manager: Anthony Khawaja

Editorial Board: Humma Shahid, Karl Mercieca, Francisco Goni

Editors in Chief: Francesco Oddone, Manuele Michelessi