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

Andrew R. Hamel, Wenjun Yan, John M. Rouhana, Aboozar Monovarfeshani, Xinyi Jiang, Puja A. Mehta, Jayshree Advani, Yuyang Luo, Qingnan Liang, Skanda Rajasundaram, Arushi Shrivastava, Katherine Duchinski, Sreekar Mantena, Jiali Wang, Tavé van Zyl, Louis R. Pasquale, Anand Swaroop, Puya Gharahkhani, Anthony P. Khawaja, Stuart MacGregor, Rui Chen, Veronique Vitart, Joshua R. Sanes, Janey L. Wiggs and Ayellet V. Segrè ()
Additional contact information
Andrew R. Hamel: Massachusetts Eye and Ear
Wenjun Yan: Harvard University
John M. Rouhana: Massachusetts Eye and Ear
Aboozar Monovarfeshani: Harvard University
Xinyi Jiang: The University of Edinburgh
Puja A. Mehta: Massachusetts Eye and Ear
Jayshree Advani: National Institutes of Health
Yuyang Luo: Massachusetts Eye and Ear
Qingnan Liang: Baylor College of Medicine
Skanda Rajasundaram: Harvard Medical School
Arushi Shrivastava: Massachusetts Eye and Ear
Katherine Duchinski: Massachusetts Eye and Ear
Sreekar Mantena: Massachusetts Eye and Ear
Jiali Wang: Massachusetts Eye and Ear
Tavé van Zyl: Harvard University
Louis R. Pasquale: Icahn School of Medicine at Mount Sinai
Anand Swaroop: National Institutes of Health
Puya Gharahkhani: QIMR Berghofer Medical Research Institute
Anthony P. Khawaja: Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology
Stuart MacGregor: QIMR Berghofer Medical Research Institute
Rui Chen: Baylor College of Medicine
Veronique Vitart: The University of Edinburgh
Joshua R. Sanes: Harvard University
Janey L. Wiggs: Massachusetts Eye and Ear
Ayellet V. Segrè: Massachusetts Eye and Ear

Nature Communications, 2024, vol. 15, issue 1, 1-25

Abstract: 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.

Date: 2024
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-023-44380-y Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-023-44380-y

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-023-44380-y

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().