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; International Glaucoma Genetics Consortium (IGGC); Rui Chen; Veronique Vitart; Joshua R Sanes; Janey L Wiggs; Ayellet V Segrè

doi:10.1038/s41467-023-44380-y

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

Nat Commun. 2024 Jan 9;15(1):396. doi: 10.1038/s41467-023-44380-y.

Authors

Andrew R Hamel^{1

2

3}, Wenjun Yan^#⁴, John M Rouhana^#^{1

2

3}, Aboozar Monovarfeshani^#⁴, Xinyi Jiang^{5

6}, Puja A Mehta^{1

2

3}, Jayshree Advani⁷, Yuyang Luo^{1

2

3}, Qingnan Liang⁸, Skanda Rajasundaram^{2

9

10}, Arushi Shrivastava^{1

2

3}, Katherine Duchinski^{1

2

3

11}, Sreekar Mantena^{1

12}, Jiali Wang^{1

2

3}, Tavé van Zyl^{4

13}, Louis R Pasquale¹⁴, Anand Swaroop⁷, Puya Gharahkhani¹⁵, Anthony P Khawaja¹⁶, Stuart MacGregor¹⁵; International Glaucoma Genetics Consortium (IGGC); Rui Chen⁸, Veronique Vitart⁵, Joshua R Sanes⁴, Janey L Wiggs^{1

2

3}, Ayellet V Segrè^{17

18

19}

Collaborators

International Glaucoma Genetics Consortium (IGGC):
Alex 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

Affiliations

¹ Ocular Genomics Institute, Department of Ophthalmology, Massachusetts Eye and Ear, Boston, MA, USA.
² Department of Ophthalmology, Harvard Medical School, Boston, MA, USA.
³ Broad Institute of Harvard and MIT, Cambridge, MA, USA.
⁴ Department of Molecular and Cellular Biology and Center for Brain Science, Harvard University, Cambridge, MA, USA.
⁵ MRC Human Genetics Unit, Institute of Genetics and Cancer, The University of Edinburgh, Edinburgh, UK.
⁶ Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, The University of Edinburgh, Edinburgh, UK.
⁷ Neurobiology, Neurodegeneration and Repair Laboratory, National Eye Institute, National Institutes of Health, Bethesda, MA, USA.
⁸ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
⁹ Centre for Evidence-Based Medicine, University of Oxford, Oxford, UK.
¹⁰ Faculty of Medicine, Imperial College London, London, UK.
¹¹ Bioinformatics and Integrative Genomics (BIG) PhD Program, Harvard Medical School, Boston, MA, USA.
¹² Harvard/MIT MD-PhD Program, Harvard Medical School, Boston, MA, USA.
¹³ Department of Ophthalmology and Visual Sciences, Yale School of Medicine, New Haven, CT, USA.
¹⁴ Department of Ophthalmology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹⁵ QIMR Berghofer Medical Research Institute, Brisbane, QLD, 4029, Australia.
¹⁶ NIHR Biomedical Research Centre, Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, London, UK.
¹⁷ Ocular Genomics Institute, Department of Ophthalmology, Massachusetts Eye and Ear, Boston, MA, USA. [email protected].
¹⁸ Department of Ophthalmology, Harvard Medical School, Boston, MA, USA. [email protected].
¹⁹ Broad Institute of Harvard and MIT, Cambridge, MA, USA. [email protected].

^# Contributed equally.

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.

MeSH terms

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

Abstract

MeSH terms

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