1. Transcriptomic and proteomic retinal pigment epithelium signatures of age-related macular degeneration
- Author
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Lisa S. Kearns, Helena Liang, Nona Farbehi, Xikun Han, Alex W. Hewitt, Drew Neavin, Grace E. Lidgerwood, Stuart MacGregor, M Isabel G Lopez Sanchez, Lerna Gulluyan, Damián Hernández, David A. Mackey, Angela Steinmann, Linda Clarke, Vivek Gupta, Louise A. Rooney, Joseph E. Powell, Alice Pébay, Chia-Ling Chan, Robyn H. Guymer, Ran Zhang, Joao A. Paulo, Maciej Daniszewski, Guy Bylsma, Uyen Nguyen, Vikkitharan Gnanasambandapillai, Rachael Zekanovic, Anne Senabouth, Nitin Verma, and Mehdi Mirzaei
- Subjects
Genetics ,Proteomics ,Multidisciplinary ,Retinal pigment epithelium ,Neurodegeneration ,General Physics and Astronomy ,General Chemistry ,Retinal Pigment Epithelium ,Biology ,Macular degeneration ,Quantitative trait locus ,medicine.disease ,General Biochemistry, Genetics and Molecular Biology ,Transcriptome ,Macular Degeneration ,medicine.anatomical_structure ,Geographic Atrophy ,Expression quantitative trait loci ,medicine ,Humans ,sense organs ,Induced pluripotent stem cell - Abstract
Induced pluripotent stem cells generated from patients with geographic atrophy as well as healthy individuals were differentiated to retinal pigment epithelium (RPE) cells. By integrating transcriptional profiles of 127,659 RPE cells generated from 43 individuals with geographic atrophy and 36 controls with genotype data, we identified 439 expression Quantitative Trait (eQTL) loci in cis that were associated with disease status and specific to subpopulations of RPE cells. We identified loci linked to two genes with known associations with geographic atrophy - PILRB and PRPH2, in addition to 43 genes with significant genotype x disease interactions that are candidates for novel genetic associations for geographic atrophy. On a transcriptome-only level, we identified molecular pathways significantly upregulated in geographic atrophy-RPE including in extracellular cellular matrix reorganisation, neurodegeneration, and mitochondrial functions. We subsequently implemented a large-scale proteomics analysis, confirming modification in proteins associated with these pathways. We also identified six significant protein (p) QTL that regulate protein expression in the RPE cells and in geographic atrophy - two of which share variants with cis-eQTL. Transcriptome-wide association analysis identified genes at loci previously associated with age-related macular degeneration. Further analysis conditional on disease status, implicated statistically significant RPE-specific eQTL. This study uncovers important differences in RPE homeostasis associated with geographic atrophy.
- Published
- 2021