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

Cell Genomics

David A. Mackey¹  Helena H. Liang¹  Jarmon G. Lees¹  Emmanuelle Souzeau¹  Joseph E. Powell¹  Damián Hernández¹  Rachael A. McCloy²  Lisa S. Kearns³  Anne Senabouth³  Lerna Gulluyan³  Shiang Y. Lim³  Stuart MacGregor³  Nona Farbehi⁴  Chia-Ling Chan⁵  Stuart L. Graham⁵  Linda Clarke⁶  Maciej Daniszewski⁶  Jordan E. Clarke⁶  Jamie E. Craig⁶  Louise Rooney⁶  Alice Pébay⁷  Grace E. Lidgerwood⁸  Uyen Nguyen⁸  Alex W. Hewitt⁹  Xikun Han^1,10  Vikkitharan Gnanasambandapillai^1,11  Priyadharshini Sivakumaran^1,12 

[1] Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, East Melbourne, VIC 3002, Australia;Department of Medicine, St Vincent’s Hospital, The University of Melbourne, Parkville, VIC 3010, Australia;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;Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, East Melbourne, VIC 3002, Australia;Department of Anatomy and Physiology, The University of Melbourne, Parkville, VIC 3010, Australia;Department of Ophthalmology, Flinders University, Flinders Medical Centre, Bedford Park, SA 5042, Australia;Department of Surgery, The University of Melbourne, Parkville, VIC 3010, Australia;Faculty of Medicine and Health Sciences, Macquarie University, Macquarie Park, NSW 2109, Australia;Garvan Weizmann Centre for Cellular Genomics, Garvan Institute of Medical Research, The Kinghorn Cancer Centre, Darlinghurst, NSW 2010, Australia;O’Brien Institute Department of St Vincent’s Institute of Medical Research, Melbourne, Fitzroy, VIC 3065, Australia;QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia;

关键词: human induced pluripotent stem cells;    retinal organoids;    retinal ganglion cells;    single-cell RNA sequencing;    glaucoma;    transcriptomics;   

DOI  :  

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown