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Retinal ganglion cell-specific genetic regulation in primary open-angle glaucoma


Daniszewski, M and Senabouth, A and Liang, HH and Han, X and Lidgerwood, GE and Hernandez, D and Sivakumaran, P and Clarke, JE and Lim, SY and Lees, JG and Rooney, L and Gulluyan, L and Souzeau, E and Graham, SL and Chan, CL and Nguyen, U and Farbehi, N and Gnanasambandapillai, V and McCloy, RA and Clarke, L and Kearns, LS and Mackey, DA and Craig, JE and MacGregor, S and Powell, JE and Pebay, A and Hewit, AW, Retinal ganglion cell-specific genetic regulation in primary open-angle glaucoma, Cell Genomics, 2, (6) Article 100142. ISSN 2666-979X (2022) [Refereed Article]

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DOI: doi:10.1016/j.xgen.2022.100142


To assess the transcriptomic profile of disease-specific cell populations, fibroblasts from patients with primary open-angle glaucoma (POAG) were reprogrammed into induced pluripotent stem cells (iPSCs) before being differentiated into retinal organoids and compared with those from healthy individuals. We performed single-cell RNA sequencing of a total of 247,520 cells and identified cluster-specific molecular signatures. Comparing the gene expression profile between cases and controls, we identified novel genetic associations for this blinding disease. Expression quantitative trait mapping identified a total of 4,443 significant loci across all cell types, 312 of which are specific to the retinal ganglion cell subpopulations, which ultimately degenerate in POAG. Transcriptome-wide association analysis identified genes at loci previously associated with POAG, and analysis, conditional on disease status, implicated 97 statistically significant retinal ganglion cell-specific expression quantitative trait loci. This work highlights the power of large-scale iPSC studies to uncover context-specific profiles for a genetically complex disease.

Item Details

Item Type:Refereed Article
Keywords:eQTL; glaucoma; human induced pluripotent stem cells; retinal ganglion cells; retinal organoids; single-cell RNA sequencing; transcriptomics.
Research Division:Biomedical and Clinical Sciences
Research Group:Ophthalmology and optometry
Research Field:Optical technology
Objective Division:Health
Objective Group:Clinical health
Objective Field:Treatment of human diseases and conditions
UTAS Author:Hewit, AW (Professor Alex Hewitt)
ID Code:155571
Year Published:2022
Deposited By:Menzies Institute for Medical Research
Deposited On:2023-03-01
Last Modified:2023-03-01

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