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

Anne Senabouth(Garvan Institute of Medical Research), Maciej Daniszewski(The University of Melbourne), Grace E. Lidgerwood(The University of Melbourne), Helena H. Liang(Centre for Eye Research Australia), 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), M. Isabel G. Lopez Sanchez(Centre for Eye Research Australia), Lerna Gulluyan(The University of Melbourne), João A. Paulo(Harvard University), Linda Clarke(Centre for Eye Research Australia), Lisa S. Kearns(Centre for Eye Research Australia), Vikkitharan Gnanasambandapillai(Garvan Institute of Medical Research), Chia‐Ling Chan(Garvan Institute of Medical Research), Uyen Nguyen(Garvan Institute of Medical Research), Angela Steinmann(Garvan Institute of Medical Research), Rachael A. McCloy(Garvan Institute of Medical Research), Nona Farbehi(Garvan Institute of Medical Research), Vivek Gupta(Macquarie University), David A. Mackey(Lions Eye Institute), Guy Bylsma(Lions Eye Institute), Nitin Verma(University of Tasmania), Stuart MacGregor(QIMR Berghofer Medical Research Institute), Matthew J. Watt(The University of Melbourne), Robyn H. Guymer(The University of Melbourne), Joseph E. Powell(Garvan Institute of Medical Research), Alex W. Hewitt(University of Tasmania), Alice Pébay(The Royal Melbourne Hospital)
Nature Communications
July 26, 2022
10.1038/s41467-022-31707-4
Cited by 64Open Access
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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.

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