Cell Genomics (Jun 2022)
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
Affiliations
- Maciej Daniszewski
- Department of Anatomy and Physiology, The University of Melbourne, Parkville, VIC 3010, Australia; Department of Surgery, The University of Melbourne, Parkville, VIC 3010, Australia; Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, East Melbourne, VIC 3002, Australia
- Anne Senabouth
- Garvan Weizmann Centre for Cellular Genomics, Garvan Institute of Medical Research, The Kinghorn Cancer Centre, Darlinghurst, NSW 2010, Australia
- Helena H. Liang
- Department of Surgery, The University of Melbourne, Parkville, VIC 3010, Australia; Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, East Melbourne, VIC 3002, Australia
- Xikun Han
- QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia
- Grace E. Lidgerwood
- Department of Anatomy and Physiology, The University of Melbourne, Parkville, VIC 3010, Australia; Department of Surgery, The University of Melbourne, Parkville, VIC 3010, Australia; Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, East Melbourne, VIC 3002, Australia
- Damián Hernández
- Department of Anatomy and Physiology, The University of Melbourne, Parkville, VIC 3010, Australia; Department of Surgery, The University of Melbourne, Parkville, VIC 3010, Australia; Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, East Melbourne, VIC 3002, Australia
- Priyadharshini Sivakumaran
- Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, East Melbourne, VIC 3002, Australia
- Jordan E. Clarke
- Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, East Melbourne, VIC 3002, Australia
- Shiang Y. Lim
- Department of Surgery, The University of Melbourne, Parkville, VIC 3010, Australia; O’Brien Institute Department of St Vincent’s Institute of Medical Research, Melbourne, Fitzroy, VIC 3065, Australia
- Jarmon G. Lees
- O’Brien Institute Department of St Vincent’s Institute of Medical Research, Melbourne, Fitzroy, VIC 3065, Australia; Department of Medicine, St Vincent’s Hospital, The University of Melbourne, Parkville, VIC 3010, Australia
- Louise Rooney
- Department of Anatomy and Physiology, The University of Melbourne, Parkville, VIC 3010, Australia; Department of Surgery, The University of Melbourne, Parkville, VIC 3010, Australia; Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, East Melbourne, VIC 3002, Australia
- Lerna Gulluyan
- Department of Anatomy and Physiology, The University of Melbourne, Parkville, VIC 3010, Australia; Department of Surgery, The University of Melbourne, Parkville, VIC 3010, Australia; Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, East Melbourne, VIC 3002, Australia
- Emmanuelle Souzeau
- Department of Ophthalmology, Flinders University, Flinders Medical Centre, Bedford Park, SA 5042, Australia
- Stuart L. Graham
- Faculty of Medicine and Health Sciences, Macquarie University, Macquarie Park, NSW 2109, Australia
- Chia-Ling Chan
- Garvan Weizmann Centre for Cellular Genomics, Garvan Institute of Medical Research, The Kinghorn Cancer Centre, Darlinghurst, NSW 2010, Australia
- Uyen Nguyen
- Garvan Weizmann Centre for Cellular Genomics, Garvan Institute of Medical Research, The Kinghorn Cancer Centre, Darlinghurst, NSW 2010, Australia
- Nona Farbehi
- Garvan Weizmann Centre for Cellular Genomics, Garvan Institute of Medical Research, The Kinghorn Cancer Centre, Darlinghurst, NSW 2010, Australia
- Vikkitharan Gnanasambandapillai
- Garvan Weizmann Centre for Cellular Genomics, Garvan Institute of Medical Research, The Kinghorn Cancer Centre, Darlinghurst, NSW 2010, Australia
- Rachael A. McCloy
- Garvan Weizmann Centre for Cellular Genomics, Garvan Institute of Medical Research, The Kinghorn Cancer Centre, Darlinghurst, NSW 2010, Australia
- Linda Clarke
- Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, East Melbourne, VIC 3002, Australia
- Lisa S. Kearns
- Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, East Melbourne, VIC 3002, Australia
- David A. Mackey
- Lions Eye Institute, Centre for Vision Sciences, University of Western Australia, Crawley, WA 6009, Australia; School of Medicine, Menzies Institute for Medical Research, University of Tasmania, Hobart, TAS 7005, Australia
- Jamie E. Craig
- Department of Ophthalmology, Flinders University, Flinders Medical Centre, Bedford Park, SA 5042, Australia
- Stuart MacGregor
- QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia
- Joseph E. Powell
- Garvan Weizmann Centre for Cellular Genomics, Garvan Institute of Medical Research, The Kinghorn Cancer Centre, Darlinghurst, NSW 2010, Australia; UNSW Cellular Genomics Futures Institute, University of New South Wales, Sydney, NSW 2052, Australia; Corresponding author
- Alice Pébay
- Department of Anatomy and Physiology, The University of Melbourne, Parkville, VIC 3010, Australia; Department of Surgery, The University of Melbourne, Parkville, VIC 3010, Australia; Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, East Melbourne, VIC 3002, Australia; Corresponding author
- Alex W. Hewitt
- Department of Surgery, The University of Melbourne, Parkville, VIC 3010, Australia; Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, East Melbourne, VIC 3002, Australia; School of Medicine, Menzies Institute for Medical Research, University of Tasmania, Hobart, TAS 7005, Australia; Corresponding author
- Journal volume & issue
-
Vol. 2,
no. 6
p. 100142
Abstract
Summary: 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.
