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, Hewitt AW, Schuster AK, Viswanathan AC, Lotery AJ, Cree AJ, Pang CP, Brandl C, Klaver CC, Hayward C, Khor CC, Cheng CY, Hammond CJ, van Duijn C, Mackey DA, Stefansson E, Vithana EN, Pasutto F, Jonansson F, Thorleifsson G, Koh J, Wilson JF, Craig JE, Vergroesen JE, Fingert JH, Jonas JB, Stefánsson K, Burdon KP, Chen LJ, Kass M, Jansonius NM, Pfeiffer N, Polašek O, Foster PJ, Mitchell P, Hysi PG, Wojciechowski R, Driessen SJ, Tompson SW, Young TL, Wong TY, Aung T, Thorsteinsdottir U, de Vries VA, Ramdas WD, Wang YX, Chen R, Vitart V, Sanes JR, Wiggs JL, Segrè AV (2024)


Publication Type: Journal article

Publication year: 2024

Journal

Book Volume: 15

Article Number: 396

Journal Issue: 1

DOI: 10.1038/s41467-023-44380-y

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.

Authors with CRIS profile

Involved external institutions

QIMR Berghofer Medical Research Institute (früher: the Queensland Institute of Medical Research) AU Australia (AU) Universitätsmedizin der Johannes Gutenberg-Universität Mainz DE Germany (DE) The Chinese University of Hong Kong (CUHK) CN China (CN) Baylor College of Medicine US United States (USA) (US) Veterans Affairs Healthcare System Boston and Harvard Medical School US United States (USA) (US) University of Tasmania (UTAS) AU Australia (AU) University Hospital Southampton NHS GB United Kingdom (GB) University of Southampton GB United Kingdom (GB) Erasmus University Medical Center (MC) NL Netherlands (NL) Genome Institute of Singapore SG Singapore (SG) University of Oxford GB United Kingdom (GB) University of Edinburgh GB United Kingdom (GB) University of Western Australia (UWA) AU Australia (AU) National University of Singapore (NUS) SG Singapore (SG) University of Iceland (UI) / Háskóli Íslands IS Iceland (IS) King’s College London GB United Kingdom (GB) deCODE genetics IS Iceland (IS) Flinders University AU Australia (AU) Capital University of Medical Sciences / 首都医科大学 CN China (CN) Harvard University US United States (USA) (US) Universitätsklinikum Regensburg DE Germany (DE) NIHR Oxford Biomedical Research Centre GB United Kingdom (GB) Icahn School of Medicine at Mount Sinai US United States (USA) (US) National Eye Institute US United States (USA) (US) Moorfields Eye Hospital NHS Foundation Trust GB United Kingdom (GB) University of Iowa US United States (USA) (US) Washington University US United States (USA) (US) University Medical Center Groningen (UMCG) / Universitair Medisch Centrum Groningen NL Netherlands (NL) University of Split / Sveučilište u Splitu HR Croatia (HR) University of Sydney (USYD) AU Australia (AU) Johns Hopkins University (JHU) US United States (USA) (US) University of Wisconsin - Madison US United States (USA) (US)

How to cite

APA:

Hamel, A.R., Yan, W., Rouhana, J.M., Monovarfeshani, A., Jiang, X., Mehta, P.A.,... Segrè, A.V. (2024). Integrating genetic regulation and single-cell expression with GWAS prioritizes causal genes and cell types for glaucoma. Nature Communications, 15(1). https://doi.org/10.1038/s41467-023-44380-y

MLA:

Hamel, Andrew R., et al. "Integrating genetic regulation and single-cell expression with GWAS prioritizes causal genes and cell types for glaucoma." Nature Communications 15.1 (2024).

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