Abstract
Background: Age-related macular degeneration (AMD) is the most common cause of visual impairment in the developed world. Despite some treatment options for late AMD, there is no intervention that blocks early AMD proceeding to the late and blinding forms. This is partly due to the lack of precise drug targets, despite great advances in genetics, epidemiology, and protein–protein interaction (PPI) networks proposed to be driving the disease pathology. A systems approach to narrow down PPI networks to specific protein drug targets would provide new therapeutic options.Materials and Methods: In this study we analyzed single cell RNAseq (RNA sequencing) datasets of 17 cell types present in choroidal, retinal pigment epithelium (RPE), and neural retina (NR) tissues to explore if a more granular analysis incorporating different cell types exposes more specific pathways and relationships. Furthermore, we developed a novel and systematic gene ontology database (SysGO) to explore if a subcellular classification of processes will further enhance the understanding of the pathogenesis of this complex disorder and its comorbidities with other age-related diseases.Results: We found that 57% of the AMD (risk) genes are among the top 25% expressed genes in ∼1 of the 17 choroidal/RPE/NR cell types, and 9% were among the top 1% of expressed genes. Using SysGO, we identified an enrichment of AMD genes in cell membrane and extracellular anatomical locations, and we found both functional enrichments (e.g., cell adhesion) and cell types (e.g., fibroblasts, microglia) not previously associated with AMD pathogenesis. We reconstructed PPI networks among the top expressed AMD genes for all 17 choroidal/RPE/NR cell types, which provides molecular and anatomical definitions of AMD phenotypes that can guide therapeutic approaches to target this complex disease.Conclusion: We provide mechanism-based AMD endophenotypes that can be exploited in vitro, using computational models and for drug discovery/repurposing.
Highlights
Age-related macular degeneration (AMD) is an eye disorder that can cause blurred, distorted, or lost central vision and is the commonest cause of blindness of elderly people.[1]
A high-confidence set of genes associated with a risk of developing AMD A list of 412 genes linked to AMD based on genome-wide association study (GWAS) studies, and family linkage and candidate gene testing studies of AMD cases versus controls were obtained from the Open Targets Platform (Fig. 1A and Supplementary Table S2)
We reasoned that individual populations of cell types within tissues could express a subset of AMD risk genes at high abundance, which would average out when measuring transcript levels in tissues, but could be detectable in single-cell expression datasets
Summary
Age-related macular degeneration (AMD) is an eye disorder that can cause blurred, distorted, or lost central vision and is the commonest cause of blindness of elderly people.[1]. Despite some treatment options for late AMD, there is no intervention that blocks early AMD proceeding to the late and blinding forms. This is partly due to the lack of precise drug targets, despite great advances in genetics, epidemiology, and protein–protein interaction (PPI) networks proposed to be driving the disease pathology. A systems approach to narrow down PPI networks to specific protein drug targets would provide new therapeutic options. We reconstructed PPI networks among the top expressed AMD genes for all 17 choroidal/RPE/NR cell types, which provides molecular and anatomical definitions of AMD phenotypes that can guide therapeutic approaches to target this complex disease. Conclusion: We provide mechanism-based AMD endophenotypes that can be exploited in vitro, using computational models and for drug discovery/repurposing
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