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

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

doi:10.1016/j.xgen.2023.100302

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

Cell Genom. 2023 Apr 18;3(6):100302. doi: 10.1016/j.xgen.2023.100302. eCollection 2023 Jun 14.

Authors

Luz D Orozco¹, Leah A Owen^{2

3

4

5}, Jeffrey Hofmann⁶, Amy D Stockwell⁷, Jianhua Tao⁶, Susan Haller⁶, Vineeth T Mukundan¹, Christine Clarke¹, Jessica Lund⁸, Akshayalakshmi Sridhar⁹, Oleg Mayba¹, Julie L Barr^{5

10}, Rylee A Zavala⁵, Elijah C Graves⁵, Charles Zhang⁵, Nadine Husami^{5

11}, Robert Finley⁵, Elizabeth Au⁵, John H Lillvis^{5

12}, Michael H Farkas^{5

10

11

12}, Akbar Shakoor², Richard Sherva¹³, Ivana K Kim¹⁴, Joshua S Kaminker¹, Michael J Townsend⁹, Lindsay A Farrer¹³, Brian L Yaspan⁷, Hsu-Hsin Chen⁹, Margaret M DeAngelis^{2

3

5

10

15}

Affiliations

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

Abstract

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.

Keywords: AMD; DNA methylation; GA; Muller glia; RNA-seq; age-related macular degeneration; epigenomics; geographic atrophy; rare variant genetics; retinal pigment epithelium; single-cell ATAC-seq; single-cell RNA-seq.

Grants and funding

K08 EY031800/EY/NEI NIH HHS/United States