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

Hamel, A. R.; Yan, W.; Rouhana, J. M.; Monovarfeshani, A.; Jiang, X.; Mehta, P. A.; Advani, J.; Luo, Y.; Liang, Q.; Rajasundaram, S.; Shrivastava, A.; Duchinski, K.; Mantena, S.; Wang, J.; van Zyl, T.; Pasquale, L. R.; Swaroop, A.; Gharahkhani, P.; Khawaja, A. P.; MacGregor, S.; Hewitt, A. W.; Schuster, A. K.; Viswanathan, A. C.; Lotery, A. J.; Cree, A. J.; Pang, C. P.; Brandl, C.; Klaver, C. C. W.; Hayward, C.; Khor, C. C.; Cheng, C. Y.; Hammond, C. J.; van Duijn, C.; Mackey, D. A.; Stefansson, E.; Vithana, E. N.; Pasutto, F.; Jonansson, F.; Thorleifsson, G.; Koh, J.; Wilson, J. F.; Craig, J. E.; Vergroesen, J. E.; Fingert, J. H.; Jonas, J. B.; Stefansson, K.; Burdon, K. P.; Chen, L. J.; Kass, M.; Jansonius, N. M.; Pfeiffer, N.; Polasek, O.; Foster, P. J.; Mitchell, Paul; Hysi, P. G.; Wojciechowski, R.; Driessen, S. J.; Tompson, S. W. J.; Young, T. L.; Wong, T. Y.; Aung, T.; Thorsteinsdottir, U.; de Vries, V. A.; Ramdas, W. D.; Wang, Y. X.; Chen, R.; Vitart, V.; Sanes, J. R.; Wiggs, J. L.; Segre, A. V.

Please use this identifier to cite or link to this item: https://wslhd.intersearch.com.au/wslhdjspui/handle/1/9484

Title:	Integrating genetic regulation and single-cell expression with GWAS prioritizes causal genes and cell types for glaucoma
Authors:	Hamel, A. R.;Yan, W.;Rouhana, J. M.;Monovarfeshani, A.;Jiang, X.;Mehta, P. A.;Advani, J.;Luo, Y.;Liang, Q.;Rajasundaram, S.;Shrivastava, A.;Duchinski, K.;Mantena, S.;Wang, J.;van Zyl, T.;Pasquale, L. R.;Swaroop, A.;Gharahkhani, P.;Khawaja, A. P.;MacGregor, S.;Hewitt, A. W.;Schuster, A. K.;Viswanathan, A. C.;Lotery, A. J.;Cree, A. J.;Pang, C. P.;Brandl, C.;Klaver, C. C. W.;Hayward, C.;Khor, C. C.;Cheng, C. Y.;Hammond, C. J.;van Duijn, C.;Mackey, D. A.;Stefansson, E.;Vithana, E. N.;Pasutto, F.;Jonansson, F.;Thorleifsson, G.;Koh, J.;Wilson, J. F.;Craig, J. E.;Vergroesen, J. E.;Fingert, J. H.;Jonas, J. B.;Stefansson, K.;Burdon, K. P.;Chen, L. J.;Kass, M.;Jansonius, N. M.;Pfeiffer, N.;Polasek, O.;Foster, P. J.;Mitchell, Paul;Hysi, P. G.;Wojciechowski, R.;Driessen, S. J.;Tompson, S. W. J.;Young, T. L.;Wong, T. Y.;Aung, T.;Thorsteinsdottir, U.;de Vries, V. A.;Ramdas, W. D.;Wang, Y. X.;Chen, R.;Vitart, V.;Sanes, J. R.;Wiggs, J. L.;Segre, A. V.
WSLHD Author:	Mitchell, Paul
Subjects:	Ophthalmology
Issue Date:	2024
Citation:	Nature Communications 15(1):396, 2024
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.
URI:	https://wslhd.intersearch.com.au/wslhdjspui/handle/1/9484
DOI:	https://dx.doi.org/10.1038/s41467-023-44380-y
Journal:	Nature Communications
Type:	Journal Article
Study or Trial:	Controlled Study Major Clinical Study
Department:	Ophthalmology
Facility:	Westmead
Affiliated Organisations:	Ocular Genomics Institute, Department of Ophthalmology, Massachusetts Eye and Ear, Boston, MA, United States Department of Ophthalmology, Harvard Medical School, Boston, MA, United States Broad Institute of Harvard and MIT, Cambridge, MA, United States Department of Molecular and Cellular Biology and Center for Brain Science, Harvard University, Cambridge, MA, United States MRC Human Genetics Unit, Institute of Genetics and Cancer, The University of Edinburgh, Edinburgh, United Kingdom Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, The University of Edinburgh, Edinburgh, United Kingdom Neurobiology, Neurodegeneration and Repair Laboratory, National Eye Institute, National Institutes of Health, Bethesda, MA, United States Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, United States Centre for Evidence-Based Medicine, University of Oxford, Oxford, United Kingdom Faculty of Medicine, Imperial College London, London, United Kingdom Bioinformatics and Integrative Genomics PhD Program, Harvard Medical School, Boston, MA, United States Harvard/MIT MD-PhD Program, Harvard Medical School, Boston, MA, United States Department of Ophthalmology and Visual Sciences, Yale School of Medicine, New Haven, CT, United States Department of Ophthalmology, Icahn School of Medicine at Mount Sinai, New York, NY, United States QIMR Berghofer Medical Research Institute, Brisbane, QLD 4029, Australia NIHR Biomedical Research Centre, Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, London, United Kingdom Menzies Institute for Medical Research, University of Tasmania, Hobart, TAS, Australia Centre for Eye Research Australia, University of Melbourne, Melbourne, VIC, Australia Department of Ophthalmology, University Medical Center Mainz, Mainz, Germany National Institute for Health Research Biomedical Research Centre, London, United Kingdom Moorfields Eye Hospital NHS Foundation Trust, London, United Kingdom UCL Institute of Ophthalmology, London, United Kingdom University Hospital Southampton NHS Foundation Trust, London, United Kingdom Faculty of Medicine, University of Southampton, Southampton, United Kingdom Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Hong Kong Department of Ophthalmology, University Hospital Regensburg, Regensburg, Germany Department of Genetic Epidemiology, University of Regensburg, Regensburg, Germany Department of Ophthalmology, Erasmus Medical Center, Rotterdam, Netherlands Department of Epidemiology, Erasmus Medical Center, Rotterdam, Netherlands Department of Ophthalmology, Radboud University Medical Center, Nijmegen, Netherlands Institute for Molecular and Clinical Ophthalmology, Basel, Switzerland Division of Human Genetics, Genome Institute of Singapore, Singapore, Singapore Singapore Eye Research Institute, Singapore National Eye Centre, Singapore, Singapore Ophthalmology & Visual Sciences Academic Clinical Program, Duke-NUS Medical School, Singapore, Singapore Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore Departments of Ophthalmology and Twin Research and Genetic Epidemiology, King's College London, London, United Kingdom Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom Department of Genetic Epidemiology, Erasmus University Medical Center, Rotterdam, Netherlands University of Western Australia, Centre for Ophthalmology and Vision Science, Lions Eye Institute, Nedlands, WA, Australia Faculty of Medicine, University of Iceland, Reykjavik, Iceland Singapore Eye Research Institute, Singapore, Singapore Institute of Human Genetics, Universitatsklinikum Erlangen, Friedrich-Alexander-Universitat Erlangen-Nurnberg, Erlangen, Germany Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland deCODE genetics/Amgen Inc., Reykjavik, Iceland Singapore National Eye Centre, Singapore, Singapore Centre for Global Health Research, Usher Institute, University of Edinburgh, Edinburgh, United Kingdom Department of Ophthalmology, Flinders University, Flinders Medical Centre, Adelaide, SA, Australia Department of Ophthalmology, Carver College of Medicine, lowa, IA, United States Institute for Vision Research, University of Iowa, lowa, IA, United States Institute of Molecular and Clinical Ophthalmology Basel, Basel, Switzerland Department of Ophthalmology, Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany Privatpraxis Prof Jonas und Dr Panda-Jonas, Heidelberg, Germany Washington University, St Louis, MO, United States Faculty of Medical Sciences, University of Groningen, Groningen, Netherlands Department of Ophthalmology, University of Groningen, Groningen, Netherlands University Medical Center Groningen, Groningen, Netherlands School of Medicine, University of Split, Split, Croatia Centre for Vision Research, Department of Ophthalmology and Westmead Institute for Medical Research, University of Sydney, Sydney, NSW, Australia Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States Department of Ophthalmology and Visual Sciences, University of Wisconsin, Madison, WI, United States Beijing Institute of Ophthalmology, Beijing Tongren Hospital, Capital Medical University, Beijing Ophthalmology and Visual Sciences Key Laboratory, Beijing, China
Keywords:	gene expression regulation genome-wide association study glaucoma
Appears in Collections:	Westmead Hospital 2019 - 2024

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