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

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 m...

Ausführliche Beschreibung

Gespeichert in:
Bibliographische Detailangaben
Veröffentlicht in:Cell genomics 2023-06, Vol.3 (6), p.100302-100302, Article 100302
Hauptverfasser: 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.
Format: Artikel
Sprache:eng
Schlagworte:
Online-Zugang:Volltext
Tags: Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
Beschreibung
Zusammenfassung: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. [Display omitted] •Bulk transcriptome and DNA methylation from RPE/choroid of phenotyped AMD eyes•Single-nucleus RNA-seq and ATAC-seq from retina, RPE, and choroid of control and AMD eyes•Single-nucleus RNA-seq and ATAC-seq prioritized putative causal genes at AMD GWAS loci•Integrative analysis identified WNT pathway regulators FRZB and TLE2 as AMD genes There is limited information on molecular changes in age-related macular degeneration (AMD), a leading cause of blindness. Orozco et al. built expression and epigenetic atlases of control and phenotyped AMD eyes at both bulk-tissue and single-cell levels. Their integrative analysis of these data unveiled genes and pathways driving disease.
ISSN:2666-979X
2666-979X
DOI:10.1016/j.xgen.2023.100302