Luthert, PJ;
Kiel, C;
(2020)
Combining Gene-Disease Associations with Single-Cell Gene Expression Data Provides Anatomy-Specific Subnetworks in Age-Related Macular Degeneration.
Network and Systems Medicine
, 3
(1)
pp. 105-121.
10.1089/nsm.2020.0005.
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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.
| Type: | Article |
|---|---|
| Title: | Combining Gene-Disease Associations with Single-Cell Gene Expression Data Provides Anatomy-Specific Subnetworks in Age-Related Macular Degeneration |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1089/nsm.2020.0005 |
| Publisher version: | https://doi.org/10.1089/nsm.2020.0005 |
| Language: | English |
| Additional information: | This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ |
| Keywords: | gene expression, gene ontology, protein–protein interaction networks, retinal degeneration |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > Institute of Ophthalmology |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10108728 |
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