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

Maciej Daniszewski; Anne Senabouth; Helena H Liang; Xikun Han; Grace E Lidgerwood; Damián Hernández; Priyadharshini Sivakumaran; Jordan E Clarke; Shiang Y Lim; Jarmon G Lees; Louise Rooney; Lerna Gulluyan; Emmanuelle Souzeau; Stuart L Graham; Chia-Ling Chan; Uyen Nguyen; Nona Farbehi; Vikkitharan Gnanasambandapillai; Rachael A McCloy; Linda Clarke; Lisa S Kearns; David A Mackey; Jamie E Craig; Stuart MacGregor; Joseph E Powell; Alice Pébay; Alex W Hewitt

doi:10.1016/j.xgen.2022.100142

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

Cell Genom. 2022 Jun 8;2(6):100142. doi: 10.1016/j.xgen.2022.100142.

Authors

Maciej Daniszewski^{1

2

3}, Anne Senabouth⁴, Helena H Liang^{2

3}, Xikun Han⁵, Grace E Lidgerwood^{1

2

3}, Damián Hernández^{1

2

3}, Priyadharshini Sivakumaran³, Jordan E Clarke³, Shiang Y Lim^{2

6}, Jarmon G Lees^{6

7}, Louise Rooney^{1

2

3}, Lerna Gulluyan^{1

2

3}, Emmanuelle Souzeau⁸, Stuart L Graham⁹, Chia-Ling Chan⁴, Uyen Nguyen⁴, Nona Farbehi⁴, Vikkitharan Gnanasambandapillai⁴, Rachael A McCloy⁴, Linda Clarke³, Lisa S Kearns³, David A Mackey^{10

11}, Jamie E Craig⁸, Stuart MacGregor⁵, Joseph E Powell^{4

12}, Alice Pébay^{1

2

3}, Alex W Hewitt^{2

3

11}

Affiliations

¹ Department of Anatomy and Physiology, The University of Melbourne, Parkville, VIC 3010, Australia.
² Department of Surgery, The University of Melbourne, Parkville, VIC 3010, Australia.
³ Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, East Melbourne, VIC 3002, Australia.
⁴ Garvan Weizmann Centre for Cellular Genomics, Garvan Institute of Medical Research, The Kinghorn Cancer Centre, Darlinghurst, NSW 2010, Australia.
⁵ QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia.
⁶ O'Brien Institute Department of St Vincent's Institute of Medical Research, Melbourne, Fitzroy, VIC 3065, Australia.
⁷ Department of Medicine, St Vincent's Hospital, The University of Melbourne, Parkville, VIC 3010, Australia.
⁸ Department of Ophthalmology, Flinders University, Flinders Medical Centre, Bedford Park, SA 5042, Australia.
⁹ Faculty of Medicine and Health Sciences, Macquarie University, Macquarie Park, NSW 2109, Australia.
¹⁰ Lions Eye Institute, Centre for Vision Sciences, University of Western Australia, Crawley, WA 6009, Australia.
¹¹ School of Medicine, Menzies Institute for Medical Research, University of Tasmania, Hobart, TAS 7005, Australia.
¹² UNSW Cellular Genomics Futures Institute, University of New South Wales, Sydney, NSW 2052, Australia.

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 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.

Keywords: eQTL; glaucoma; human induced pluripotent stem cells; retinal ganglion cells; retinal organoids; single-cell RNA sequencing; transcriptomics.