Transcriptomic and proteomic retinal pigment epithelium signatures of age-related macular degeneration

Anne Senabouth, Maciej Daniszewski, Grace E. Lidgerwood, Helena H. Liang, Damián Hernández, Mehdi Mirzaei, Stacey N. Keenan, Ran Zhang, Xikun Han, Drew Neavin, Louise Rooney, Maria Isabel G. Lopez Sanchez, Lerna Gulluyan, Joao A. Paulo, Linda Clarke, Lisa S. Kearns, Vikkitharan Gnanasambandapillai, Chia-Ling Chan, Uyen Nguyen, Angela M. Steinmann, Rachael A. McCloy, Nona Farbehi, Vivek K. Gupta, David A. Mackey, Guy Bylsma, Nitin Verma, Stuart MacGregor, Matthew J. Watt, Robyn H. Guymer, Joseph E. Powell (), Alex W. Hewitt () and Alice Pébay ()
Additional contact information
Anne Senabouth: Garvan Institute of Medical Research
Maciej Daniszewski: The University of Melbourne
Grace E. Lidgerwood: The University of Melbourne
Helena H. Liang: Royal Victorian Eye and Ear Hospital
Damián Hernández: The University of Melbourne
Mehdi Mirzaei: Macquarie University
Stacey N. Keenan: The University of Melbourne
Ran Zhang: Garvan Institute of Medical Research
Xikun Han: QIMR Berghofer Medical Research Institute
Drew Neavin: Garvan Institute of Medical Research
Louise Rooney: The University of Melbourne
Maria Isabel G. Lopez Sanchez: Royal Victorian Eye and Ear Hospital
Lerna Gulluyan: The University of Melbourne
Joao A. Paulo: Harvard Medical School
Linda Clarke: Royal Victorian Eye and Ear Hospital
Lisa S. Kearns: Royal Victorian Eye and Ear Hospital
Vikkitharan Gnanasambandapillai: Garvan Institute of Medical Research
Chia-Ling Chan: Garvan Institute of Medical Research
Uyen Nguyen: Garvan Institute of Medical Research
Angela M. Steinmann: Garvan Institute of Medical Research
Rachael A. McCloy: Garvan Institute of Medical Research
Nona Farbehi: Garvan Institute of Medical Research
Vivek K. Gupta: Macquarie University
David A. Mackey: University of Western Australia
Guy Bylsma: University of Western Australia
Nitin Verma: University of Tasmania
Stuart MacGregor: QIMR Berghofer Medical Research Institute
Matthew J. Watt: The University of Melbourne
Robyn H. Guymer: Royal Victorian Eye and Ear Hospital
Joseph E. Powell: Garvan Institute of Medical Research
Alex W. Hewitt: Royal Victorian Eye and Ear Hospital
Alice Pébay: The University of Melbourne

Nature Communications, 2022, vol. 13, issue 1, 1-18

Abstract: Abstract There are currently no treatments for geographic atrophy, the advanced form of age-related macular degeneration. Hence, innovative studies are needed to model this condition and prevent or delay its progression. Induced pluripotent stem cells generated from patients with geographic atrophy and healthy individuals were differentiated to retinal pigment epithelium. Integrating transcriptional profiles of 127,659 retinal pigment epithelium cells generated from 43 individuals with geographic atrophy and 36 controls with genotype data, we identify 445 expression quantitative trait loci in cis that are asssociated with disease status and specific to retinal pigment epithelium subpopulations. Transcriptomics and proteomics approaches identify molecular pathways significantly upregulated in geographic atrophy, including in mitochondrial functions, metabolic pathways and extracellular cellular matrix reorganization. Five significant protein quantitative trait loci that regulate protein expression in the retinal pigment epithelium and in geographic atrophy are identified - two of which share variants with cis- expression quantitative trait loci, including proteins involved in mitochondrial biology and neurodegeneration. Investigation of mitochondrial metabolism confirms mitochondrial dysfunction as a core constitutive difference of the retinal pigment epithelium from patients with geographic atrophy. This study uncovers important differences in retinal pigment epithelium homeostasis associated with geographic atrophy.

Date: 2022
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DOI: 10.1038/s41467-022-31707-4

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