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 MacGregorAlex W. Hewitt, Alexander K. Schuster, Ananth C. Viswanathan, Andrew J. Lotery, Angela J. Cree, Calvin P. Pang, Caroline Brandl, Caroline C.W. Klaver, Caroline Hayward, Chiea Chuen Khor, Ching Yu Cheng, Christopher J. Hammond, Cornelia van Duijn, David A. Mackey, Einer Stefansson, Eranga N. Vithana, Francesca Pasutto, Fridbert Jonansson, Gudmar Thorleifsson, Jacyline Koh, James F. Wilson, Jamie E. Craig, Joëlle E. Vergroesen, John H. Fingert, Jost B. Jonas, Kári Stefánsson, Kathryn P. Burdon, Li Jia Chen, Michael Kass, Nomdo M. Jansonius, Norbert Pfeiffer, Ozren Polašek, Paul J. Foster, Paul Mitchell, Pirro G. Hysi, Robert Wojciechowski, Sjoerd J. Driessen, Stuart W.J. Tompson, Terri L. Young, Tien Y. Wong, Tin Aung, Unnur Thorsteinsdottir, Victor A. de Vries, Wishal D. Ramdas, Ya Xing Wang, Rui Chen, Veronique Vitart, Joshua R. Sanes, Janey L. Wiggs, Ayellet V. Segrè*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Article number396
Pages (from-to)396
JournalNature Communications
Issue number1
Publication statusPublished - 9 Jan 2024

Bibliographical note

© 2024. The Author(s).

Other keywords

  • Humans
  • Genome-Wide Association Study
  • Glaucoma, Open-Angle/genetics
  • Gene Expression Regulation
  • Causality
  • Glaucoma/genetics


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