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

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://dx.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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