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

Autor:	Hamel AR; Ocular Genomics Institute, Department of Ophthalmology, Massachusetts Eye and Ear, Boston, MA, USA.; Department of Ophthalmology, Harvard Medical School, Boston, MA, USA.; Broad Institute of Harvard and MIT, Cambridge, MA, USA., Yan W; Department of Molecular and Cellular Biology and Center for Brain Science, Harvard University, Cambridge, MA, USA., Rouhana JM; Ocular Genomics Institute, Department of Ophthalmology, Massachusetts Eye and Ear, Boston, MA, USA.; Department of Ophthalmology, Harvard Medical School, Boston, MA, USA.; Broad Institute of Harvard and MIT, Cambridge, MA, USA., Monovarfeshani A; Department of Molecular and Cellular Biology and Center for Brain Science, Harvard University, Cambridge, MA, USA., Jiang X; MRC Human Genetics Unit, Institute of Genetics and Cancer, The University of Edinburgh, Edinburgh, UK.; Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, The University of Edinburgh, Edinburgh, UK., Mehta PA; Ocular Genomics Institute, Department of Ophthalmology, Massachusetts Eye and Ear, Boston, MA, USA.; Department of Ophthalmology, Harvard Medical School, Boston, MA, USA.; Broad Institute of Harvard and MIT, Cambridge, MA, USA., Advani J; Neurobiology, Neurodegeneration and Repair Laboratory, National Eye Institute, National Institutes of Health, Bethesda, MA, USA., Luo Y; Ocular Genomics Institute, Department of Ophthalmology, Massachusetts Eye and Ear, Boston, MA, USA.; Department of Ophthalmology, Harvard Medical School, Boston, MA, USA.; Broad Institute of Harvard and MIT, Cambridge, MA, USA., Liang Q; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA., Rajasundaram S; Department of Ophthalmology, Harvard Medical School, Boston, MA, USA.; Centre for Evidence-Based Medicine, University of Oxford, Oxford, UK.; Faculty of Medicine, Imperial College London, London, UK., Shrivastava A; Ocular Genomics Institute, Department of Ophthalmology, Massachusetts Eye and Ear, Boston, MA, USA.; Department of Ophthalmology, Harvard Medical School, Boston, MA, USA.; Broad Institute of Harvard and MIT, Cambridge, MA, USA., Duchinski K; Ocular Genomics Institute, Department of Ophthalmology, Massachusetts Eye and Ear, Boston, MA, USA.; Department of Ophthalmology, Harvard Medical School, Boston, MA, USA.; Broad Institute of Harvard and MIT, Cambridge, MA, USA.; Bioinformatics and Integrative Genomics (BIG) PhD Program, Harvard Medical School, Boston, MA, USA., Mantena S; Ocular Genomics Institute, Department of Ophthalmology, Massachusetts Eye and Ear, Boston, MA, USA.; Harvard/MIT MD-PhD Program, Harvard Medical School, Boston, MA, USA., Wang J; Ocular Genomics Institute, Department of Ophthalmology, Massachusetts Eye and Ear, Boston, MA, USA.; Department of Ophthalmology, Harvard Medical School, Boston, MA, USA.; Broad Institute of Harvard and MIT, Cambridge, MA, USA., van Zyl T; Department of Molecular and Cellular Biology and Center for Brain Science, Harvard University, Cambridge, MA, USA.; Department of Ophthalmology and Visual Sciences, Yale School of Medicine, New Haven, CT, USA., Pasquale LR; Department of Ophthalmology, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Swaroop A; Neurobiology, Neurodegeneration and Repair Laboratory, National Eye Institute, National Institutes of Health, Bethesda, MA, USA., Gharahkhani P; QIMR Berghofer Medical Research Institute, Brisbane, QLD, 4029, Australia., Khawaja AP; NIHR Biomedical Research Centre, Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, London, UK., MacGregor S; QIMR Berghofer Medical Research Institute, Brisbane, QLD, 4029, Australia., Chen R; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA., Vitart V; MRC Human Genetics Unit, Institute of Genetics and Cancer, The University of Edinburgh, Edinburgh, UK., Sanes JR; Department of Molecular and Cellular Biology and Center for Brain Science, Harvard University, Cambridge, MA, USA., Wiggs JL; Ocular Genomics Institute, Department of Ophthalmology, Massachusetts Eye and Ear, Boston, MA, USA.; Department of Ophthalmology, Harvard Medical School, Boston, MA, USA.; Broad Institute of Harvard and MIT, Cambridge, MA, USA., Segrè AV; Ocular Genomics Institute, Department of Ophthalmology, Massachusetts Eye and Ear, Boston, MA, USA. ayellet_segre@meei.harvard.edu.; Department of Ophthalmology, Harvard Medical School, Boston, MA, USA. ayellet_segre@meei.harvard.edu.; Broad Institute of Harvard and MIT, Cambridge, MA, USA. ayellet_segre@meei.harvard.edu.
Jazyk:	angličtina
Zdroj:	Nature communications [Nat Commun] 2024 Jan 09; Vol. 15 (1), pp. 396. Date of Electronic Publication: 2024 Jan 09.
DOI:	10.1038/s41467-023-44380-y
Abstrakt:	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. (© 2024. The Author(s).)
Databáze:	MEDLINE
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