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

Cell Genomics · 29 authors, 15 centres

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TL;DR

This study created a multi-omic molecular atlas of human donor eyes to identify novel disease mechanisms in age-related macular degeneration (AMD). The key finding was the discovery of a distinct Müller glia state in AMD and the identification of novel regulatory genes, including WNT pathway regulators *FRZB* and *TLE2*, as potential mechanistic players.

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The researchers performed a comprehensive systems biology analysis using bulk RNA sequencing and DNA methylation from macular retinal pigment epithelium/choroid of 85 donors, and single-nucleus RNA-seq and ATAC-seq from the retina, RPE, and choroid of 6 AMD and 7 control donors. They identified over 1,000 differentially expressed genes across disease stages and 23 genome-wide significant differentially methylated loci. The study also highlighted the WNT signaling pathway, identifying *FRZB* and *TLE2* as negative regulators with differential methylation and expression in AMD.

STUDY TYPE

other

SPECIALTY

ophthalmology

SUMMARISED BY

AI pipeline

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100% · A

ORIGINAL PAPER

PMC10300496

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

Cell Genomics

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ABSTRACT

Summary 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.

CITATION EXPORT

Luz D. Orozco, Leah A. Owen, Jeffrey Hofmann et al.. A systems biology approach uncovers novel disease mechanisms in age-related macular degeneration. Cell Genomics. (2023). https://doi.org/10.1016/j.xgen.2023.100302

AUTHORS

29 · 15 CENTRES

Luz D. Orozco, Leah A. Owen, Jeffrey Hofmann, Amy D. Stockwell, Jianhua Tao, Susan Haller, Vineeth T. Mukundan, Christine Clarke, Jessica Lund, Akshayalakshmi Sridhar, Oleg Mayba, Julie L. Barr, Rylee A. Zavala, Elijah C. Graves, Charles Zhang, Nadine Husami, Robert Finley, Elizabeth Au, John H. Lillvis, Michael H. Farkas, Akbar Shakoor, Richard Sherva, Ivana K. Kim, Joshua S. Kaminker, Michael J. Townsend, Lindsay A. Farrer, Brian L. Yaspan, Hsu-Hsin Chen, Margaret M. DeAngelis

1Department of Bioinformatics and Computational Biology, Genentech, South San Francisco, CA 94080, USA
2Department of Ophthalmology and Visual Sciences, University of Utah School of Medicine, The University of Utah, Salt Lake City, UT 84132, USA
3Department of Population Health Sciences, University of Utah School of Medicine, The University of Utah, Salt Lake City, UT 84132, USA
4Department of Obstetrics and Gynecology, University of Utah School of Medicine, The University of Utah, Salt Lake City, UT 84132, USA
5Department of Ophthalmology, Ross Eye Institute, Jacobs School of Medicine and Biomedical Sciences, State University of New York, University at Buffalo, Buffalo, NY 14203, USA
6Department of Pathology, Genentech, South San Francisco, CA 94080, USA
7Department of Human Genetics, Genentech, South San Francisco, CA 94080, USA
8Departments of Microchemistry, Proteomics and Lipidomics, Genentech, South San Francisco, CA 94080, USA
9Department of Human Pathobiology & OMNI Reverse Translation, Genentech, South San Francisco, CA 94080, USA
10Neuroscience Graduate Program, Jacobs School of Medicine and Biomedical Sciences, State University of New York, University at Buffalo, Buffalo, NY 14203, USA
11Department of Biochemistry, Jacobs School of Medicine and Biomedical Sciences, State University of New York, University at Buffalo, Buffalo, NY 14203, USA
12Veterans Administration Western New York Healthcare System, Buffalo, NY 14212, USA
13Department of Medicine, Biomedical Genetics, Boston University School of Medicine, Boston, MA 02118, USA
14Retina Service, Massachusetts Eye & Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA 02114, USA
15Genetics, Genomics and Bioinformatics Graduate Program, Jacobs School of Medicine and Biomedical Sciences, State University of New York, University at Buffalo, Buffalo, NY 14203, USA