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

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

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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