Centre for Eye Research Australia (CERA) - Research Publications

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Author: Daniszewski, Maciej × Author: Hewitt, Alexander × Author: Mackey, David × End date: 2024 × Start date: 2020 ×

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    Retinal ganglion cell-specific genetic regulation in primary open-angle glaucoma
    Daniszewski, M ; Senabouth, A ; Liang, HH ; Han, X ; Lidgerwood, GE ; Hernandez, D ; Sivakumaran, P ; Clarke, JE ; Lim, SY ; Lees, JG ; Rooney, L ; Gulluyan, L ; Souzeau, E ; Graham, SL ; Chan, C-L ; Nguyen, U ; Farbehi, N ; Gnanasambandapillai, V ; Mccloy, RA ; Clarke, L ; Kearns, LS ; Mackey, DA ; Craig, JE ; Macgregor, S ; Powell, JE ; Pebay, A ; Hewitt, AW (ELSEVIER, 2022-06-08)
    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.
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    Transcriptomic and proteomic retinal pigment epithelium signatures of age-related macular degeneration
    Senabouth, A ; Daniszewski, M ; Lidgerwood, GE ; Liang, HH ; Hernandez, D ; Mirzaei, M ; Keenan, SN ; Zhang, R ; Han, X ; Neavin, D ; Rooney, L ; Sanchez, MIGL ; Gulluyan, L ; Paulo, JA ; Clarke, L ; Kearns, LS ; Gnanasambandapillai, V ; Chan, C-L ; Nguyen, U ; Steinmann, AM ; McCloy, RA ; Farbehi, N ; Gupta, VK ; Mackey, DA ; Bylsma, G ; Verma, N ; MacGregor, S ; Watt, MJ ; Guymer, RH ; Powell, JE ; Hewitt, AW ; Pebay, A (NATURE PORTFOLIO, 2022-07-26)
    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.