A systems biology approach uncovers novel disease mechanisms in age-related macular degeneration.

Autor:	Orozco LD; Department of Bioinformatics and Computational Biology, Genentech, South San Francisco, CA 94080, USA., Owen LA; Department of Ophthalmology and Visual Sciences, University of Utah School of Medicine, The University of Utah, Salt Lake City, UT 84132, USA.; Department of Population Health Sciences, University of Utah School of Medicine, The University of Utah, Salt Lake City, UT 84132, USA.; Department of Obstetrics and Gynecology, University of Utah School of Medicine, The University of Utah, Salt Lake City, UT 84132, USA.; Department of Ophthalmology, Ross Eye Institute, Jacobs School of Medicine and Biomedical Sciences, State University of New York, University at Buffalo, Buffalo, NY 14203, USA., Hofmann J; Department of Pathology, Genentech, South San Francisco, CA 94080, USA., Stockwell AD; Department of Human Genetics, Genentech, South San Francisco, CA 94080, USA., Tao J; Department of Pathology, Genentech, South San Francisco, CA 94080, USA., Haller S; Department of Pathology, Genentech, South San Francisco, CA 94080, USA., Mukundan VT; Department of Bioinformatics and Computational Biology, Genentech, South San Francisco, CA 94080, USA., Clarke C; Department of Bioinformatics and Computational Biology, Genentech, South San Francisco, CA 94080, USA., Lund J; Departments of Microchemistry, Proteomics and Lipidomics, Genentech, South San Francisco, CA 94080, USA., Sridhar A; Department of Human Pathobiology & OMNI Reverse Translation, Genentech, South San Francisco, CA 94080, USA., Mayba O; Department of Bioinformatics and Computational Biology, Genentech, South San Francisco, CA 94080, USA., Barr JL; Department of Ophthalmology, Ross Eye Institute, Jacobs School of Medicine and Biomedical Sciences, State University of New York, University at Buffalo, Buffalo, NY 14203, USA.; Neuroscience Graduate Program, Jacobs School of Medicine and Biomedical Sciences, State University of New York, University at Buffalo, Buffalo, NY 14203, USA., Zavala RA; Department of Ophthalmology, Ross Eye Institute, Jacobs School of Medicine and Biomedical Sciences, State University of New York, University at Buffalo, Buffalo, NY 14203, USA., Graves EC; Department of Ophthalmology, Ross Eye Institute, Jacobs School of Medicine and Biomedical Sciences, State University of New York, University at Buffalo, Buffalo, NY 14203, USA., Zhang C; Department of Ophthalmology, Ross Eye Institute, Jacobs School of Medicine and Biomedical Sciences, State University of New York, University at Buffalo, Buffalo, NY 14203, USA., Husami N; Department of Ophthalmology, Ross Eye Institute, Jacobs School of Medicine and Biomedical Sciences, State University of New York, University at Buffalo, Buffalo, NY 14203, USA.; Department of Biochemistry, Jacobs School of Medicine and Biomedical Sciences, State University of New York, University at Buffalo, Buffalo, NY 14203, USA., Finley R; Department of Ophthalmology, Ross Eye Institute, Jacobs School of Medicine and Biomedical Sciences, State University of New York, University at Buffalo, Buffalo, NY 14203, USA., Au E; Department of Ophthalmology, Ross Eye Institute, Jacobs School of Medicine and Biomedical Sciences, State University of New York, University at Buffalo, Buffalo, NY 14203, USA., Lillvis JH; Department of Ophthalmology, Ross Eye Institute, Jacobs School of Medicine and Biomedical Sciences, State University of New York, University at Buffalo, Buffalo, NY 14203, USA.; Veterans Administration Western New York Healthcare System, Buffalo, NY 14212, USA., Farkas MH; Department of Ophthalmology, Ross Eye Institute, Jacobs School of Medicine and Biomedical Sciences, State University of New York, University at Buffalo, Buffalo, NY 14203, USA.; Neuroscience Graduate Program, Jacobs School of Medicine and Biomedical Sciences, State University of New York, University at Buffalo, Buffalo, NY 14203, USA.; Department of Biochemistry, Jacobs School of Medicine and Biomedical Sciences, State University of New York, University at Buffalo, Buffalo, NY 14203, USA.; Veterans Administration Western New York Healthcare System, Buffalo, NY 14212, USA., Shakoor A; Department of Ophthalmology and Visual Sciences, University of Utah School of Medicine, The University of Utah, Salt Lake City, UT 84132, USA., Sherva R; Department of Medicine, Biomedical Genetics, Boston University School of Medicine, Boston, MA 02118, USA., Kim IK; Retina Service, Massachusetts Eye & Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA 02114, USA., Kaminker JS; Department of Bioinformatics and Computational Biology, Genentech, South San Francisco, CA 94080, USA., Townsend MJ; Department of Human Pathobiology & OMNI Reverse Translation, Genentech, South San Francisco, CA 94080, USA., Farrer LA; Department of Medicine, Biomedical Genetics, Boston University School of Medicine, Boston, MA 02118, USA., Yaspan BL; Department of Human Genetics, Genentech, South San Francisco, CA 94080, USA., Chen HH; Department of Human Pathobiology & OMNI Reverse Translation, Genentech, South San Francisco, CA 94080, USA., DeAngelis MM; Department of Ophthalmology and Visual Sciences, University of Utah School of Medicine, The University of Utah, Salt Lake City, UT 84132, USA.; Department of Population Health Sciences, University of Utah School of Medicine, The University of Utah, Salt Lake City, UT 84132, USA.; Department of Ophthalmology, Ross Eye Institute, Jacobs School of Medicine and Biomedical Sciences, State University of New York, University at Buffalo, Buffalo, NY 14203, USA.; Neuroscience Graduate Program, Jacobs School of Medicine and Biomedical Sciences, State University of New York, University at Buffalo, Buffalo, NY 14203, USA.; Genetics, Genomics and Bioinformatics Graduate Program, Jacobs School of Medicine and Biomedical Sciences, State University of New York, University at Buffalo, Buffalo, NY 14203, USA.
Jazyk:	angličtina
Zdroj:	Cell genomics [Cell Genom] 2023 Apr 18; Vol. 3 (6), pp. 100302. Date of Electronic Publication: 2023 Apr 18 (Print Publication: 2023).
DOI:	10.1016/j.xgen.2023.100302
Abstrakt:	Age-related macular degeneration (AMD) is a leading cause of blindness, affecting 200 million people worldwide. To identify genes that could be targeted for treatment, we created a molecular atlas at different stages of AMD. Our resource is comprised of RNA sequencing (RNA-seq) and DNA methylation microarrays from bulk macular retinal pigment epithelium (RPE)/choroid of clinically phenotyped normal and AMD donor eyes (n = 85), single-nucleus RNA-seq (164,399 cells), and single-nucleus assay for transposase-accessible chromatin (ATAC)-seq (125,822 cells) from the retina, RPE, and choroid of 6 AMD and 7 control donors. We identified 23 genome-wide significant loci differentially methylated in AMD, over 1,000 differentially expressed genes across different disease stages, and an AMD Müller state distinct from normal or gliosis. Chromatin accessibility peaks in genome-wide association study (GWAS) loci revealed putative causal genes for AMD, including HTRA1 and C6orf223 . Our systems biology approach uncovered molecular mechanisms underlying AMD, including regulators of WNT signaling, FRZB and TLE2 , as mechanistic players in disease. Competing Interests: L.D.O., J.H., A.D.S., J.T., S.H., V.T.M., C.C., J.L., A. Sridhar, O.M., J.S.K., M.J.T., B.L.Y., and H.-H.C. are employees and shareholders of Genentech/Roche. I.K.K. is a consultant for Kodiak Sciences and Biophytis and receives research funding from Allergen. M.M.D. has a research grant from Genentech/Roche. (© 2023 The Authors.)
Databáze:	MEDLINE
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