@article{8a7523ace5ef47d5a782f13bee00c755,
title = "Transcriptomic and proteomic retinal pigment epithelium signatures of age-related macular degeneration",
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 associated 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.",
author = "Anne Senabouth and Maciej Daniszewski and Lidgerwood, {Grace E.} and Liang, {Helena H.} and Dami{\'a}n Hern{\'a}ndez and Mehdi Mirzaei and Keenan, {Stacey N.} and Ran Zhang and Xikun Han and Drew Neavin and Louise Rooney and {Lopez Sanchez}, {Maria Isabel G.} and Lerna Gulluyan and Paulo, {Joao A.} and Linda Clarke and Kearns, {Lisa S.} and Vikkitharan Gnanasambandapillai and Chan, {Chia Ling} and Uyen Nguyen and Steinmann, {Angela M.} and McCloy, {Rachael A.} and Nona Farbehi and Gupta, {Vivek K.} and Mackey, {David A.} and Guy Bylsma and Nitin Verma and Stuart MacGregor and Watt, {Matthew J.} and Guymer, {Robyn H.} and Powell, {Joseph E.} and Hewitt, {Alex W.} and Alice P{\'e}bay",
note = "Funding Information: We thank all participants who donated skin biopsies. This research was supported by National Health and Medical Research Council (NHMRC) Practitioner Fellowship (A.W.H.), Senior Research Fellowship (A.P., 1154389; S.M., 1154543), and Investigator grant (J.E.P., 1175781), by research grants from the Macular Disease Foundation Australia (R.H.G., A.W.H., J.E.P., and A.P.), the NHMRC (research grant 1059369, R.H.G., A.P., synergy grant 1181010, R.H.G. and A.P.), the DHB Foundation (G.E.L. and A.P.), retina Australia (A.W.H. and A.P.), Australian Vision Research (G.E.L., A.W.H., and A.P.), the Medical Research Future Fund—Stem Cell Therapies Mission (G.E.L., A.W.H., and A.P., MRF1200678), NIH/NIGMS grant R01 (J.A.P., GM132129), the University of Melbourne and Operational Infrastructure Support from the Victorian Government. Publisher Copyright: {\textcopyright} 2022, The Author(s).",
year = "2022",
month = dec,
doi = "10.1038/s41467-022-31707-4",
language = "English",
volume = "13",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group - Macmillan Publishers",
number = "1",
}