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Retinal ganglion cell-specific genetic regulation in primary open-angle glaucoma
journal contributionposted on 2023-02-08, 03:05 authored by M Daniszewski, A Senabouth, HH Liang, X Han, GE Lidgerwood, D Hernández, P Sivakumaran, JE Clarke, SY Lim, JG Lees, L Rooney, L Gulluyan, E Souzeau, SL Graham, CL Chan, U Nguyen, N Farbehi, V Gnanasambandapillai, RA McCloy, L Clarke, LS Kearns, DA Mackey, JE Craig, S MacGregor, JE Powell, A Pébay, AW Hewitt
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.