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

Hamel, Andrew R; Yan, Wenjun; Rouhana, John M; Monovarfeshani, Aboozar; Jiang, Xinyi; Mehta, Puja A; Advani, Jayshree; ... Segrè, Ayellet V; + view all (2024) Integrating genetic regulation and single-cell expression with GWAS prioritizes causal genes and cell types for glaucoma. Nature Communications , 15 , Article 396. 10.1038/s41467-023-44380-y. (In press). Green open access

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Abstract

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.

Type: Article
Title: Integrating genetic regulation and single-cell expression with GWAS prioritizes causal genes and cell types for glaucoma
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.1038/s41467-023-44380-y
Publisher version: https://doi.org/10.1038/s41467-023-44380-y
Language: English
Additional information: © The Author(s), 2024. This is an Open Access article distributed under the terms of the Creative Commons Attribution Licence (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. https://creativecommons.org/licenses/by/4.0/
Keywords: Functional genomics, Optic nerve diseases, Statistical methods
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > Institute of Ophthalmology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Population, Policy and Practice Dept
URI: https://discovery.ucl.ac.uk/id/eprint/10185570
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