1. Retinal ganglion cell-specific genetic regulation in primary open angle glaucoma
- Author
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Craig Jee, Gnanasambandapillai, Stuart MacGregor, David A. Mackey, Damián Hernández, Xikun Han, Alex W. Hewitt, Uyen Nguyen, Joseph E. Powell, Lisa S. Kearns, Helena Liang, Nona Farbehi, Shiang Y. Lim, Clarke Je, Chia-Ling Chan, Grace E. Lidgerwood, Alice Pébay, Stuart L. Graham, Lerna Gulluyan, Maciej S. Daniszewski, Louise A. Rooney, Anne Senabouth, Emmanuelle Souzeau, Jarmon G Lees, Linda Clarke, Priyadharshini Sivakumaran, and Rachael A. McCloy
- Subjects
Genetics ,Cell type ,Retinal ,Quantitative trait locus ,Biology ,Retinal ganglion ,chemistry.chemical_compound ,medicine.anatomical_structure ,Retinal ganglion cell ,chemistry ,Expression quantitative trait loci ,medicine ,Induced pluripotent stem cell ,Genetic association - Abstract
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 to those from healthy individuals. We performed single-cell RNA-sequencing of a total of 330,569 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 2,235 significant loci across all cell types, 58 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 54 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.
- Published
- 2021