Cell genomics · 2023
A systems biology approach uncovers novel disease mechanisms in age-related macular degeneration.
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Orozco Luz D, Owen Leah A, Hofmann Jeffrey, Stockwell Amy D, Tao Jianhua, Haller Susan, Mukundan Vineeth T, Clarke Christine, Lund Jessica, Sridhar Akshayalakshmi, Mayba Oleg, Barr Julie L, Zavala Rylee A, Graves Elijah C, Zhang Charles, Husami Nadine, Finley Robert, Au Elizabeth, Lillvis John H, Farkas Michael H, Shakoor Akbar, Sherva Richard, Kim Ivana K, Kaminker Joshua S, Townsend Michael J, Farrer Lindsay A, Yaspan Brian L, Chen Hsu-Hsin, DeAngelis Margaret M
Аннотация
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.