Retinal ganglion cell-specific genetic regulation in primary open angle glaucoma

Daniszewski, Maciej; Senabouth, Anne; Hh, Liang; Han, Xing; Ge, Lidgerwood; Hernández, Damián; Sivakumaran, Priyadharshini; Je, Clarke; Sy, Lim; Jg, Lees; Rooney, Louise; Gulluyan, Lerna; Souzeau, Emmanuelle; Sl, Graham; Chan, Chia-Ling; Nguyen, Uyen; Farbehi, Nona; Gnanasambandapillai,; Ra, McCloy; Clarke, Linda; Kearns, Lisa S.; Da, Mackey; Jee, Craig; MacGregor, Stuart; Powell, Joseph E.; Pébay, Alice; Aw, Hewitt

doi:10.1101/2021.07.14.452417

Cited by 3 publications

(4 citation statements)

References 99 publications

(108 reference statements)

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“…1 and 2 ). We matched these iPSCs with control iPSC lines from ethnically matched healthy individuals that were generated and characterized in a previous study 44 (Supplementary Figs. 1 and 2 , and Supplementary Data 1 ).…”

Section: Resultsmentioning

confidence: 99%

“…The majority of genes with an eQTL (eGenes) (62.9%) were subpopulation-exclusive, and only two eGenes— GSTT1 and RPS26 —were common to all subpopulations. RPS26 , which encodes for proteins forming the small subunits of ribosomes, was found to be ubiquitous in iPSC-derived retinal organoids 44 and has been associated with type 1 diabetes 71 . Two eQTL associated with this gene—rs1131017 27 from RPE3, and rs10876864 25 from RPE1 and RPE2 have been previously characterized in bulk studies.…”

Section: Resultsmentioning

confidence: 99%

“…The control cohort has previously been described in ref. 44 , and had no manifest ophthalmic disease or drusen. The mean ± SD age at recruitment for participants was 69.8 ± 9.5 years.…”

Section: Methodsmentioning

confidence: 99%

“…Only geographic atrophy lines were generated for this study, as all control lines were already generated, and characterized in ref. 44 .…”

Section: Methodsmentioning

confidence: 99%

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

et al. 2022

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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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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

“…The control cohort has previously been described in ref. 44 , and had no manifest ophthalmic disease or drusen. The mean ± SD age at recruitment for participants was 69.8 ± 9.5 years.…”

Section: Methodsmentioning

confidence: 99%

“…Only geographic atrophy lines were generated for this study, as all control lines were already generated, and characterized in ref. 44 .…”

Section: Methodsmentioning

confidence: 99%

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

et al. 2022

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Village in a dish: a model system for population-scale hiPSC studies

Neavin

Steinmann

Chiu

et al. 2021

Preprint

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The mechanisms by which DNA alleles contribute to disease risk, drug response, and other human phenotypes are highly context-specific, varying across cell types and under different conditions. Human induced pluripotent stem cells (hiPSCs) are uniquely suited to study these context-dependent effects, but to do so requires cell lines from hundreds or potentially thousands of individuals. Village cultures, where multiple hiPSC lines are cultured and differentiated together in a single dish, provide an elegant solution for scaling hiPSC experiments to the necessary sample sizes required for population-scale studies. Here, we show the utility of village models, demonstrating how cells can be assigned back to a donor line using single cell sequencing, and addressing whether line-specific signaling alters the transcriptional profiles of companion lines in a village culture. We generated single cell RNA sequence data from hiPSC lines cultured independently (uni-culture) and in villages at three independent sites. We show that the transcriptional profiles of hiPSC lines are highly consistent between uni- and village cultures for both fresh (0.46 < R < 0.88) and cryopreserved samples (0.46 < R < 0.62). Using a mixed linear model framework, we estimate that the proportion of transcriptional variation across cells is predominantly due to donor effects, with minimal evidence of variation due to culturing in a village system. We demonstrate that the genetic, epigenetic or hiPSC line-specific effects on gene expression are consistent whether the lines are uni- or village-cultured (0.82 < R < 0.94). Finally, we identify the consistency in the landscape of cell states between uni- and village-culture systems. Collectively, we demonstrate that village methods can be effectively used to detect hiPSC line-specific effects including sensitive dynamics of cell states.

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

Senabouth

Daniszewski

Lidgerwood

et al. 2021

Preprint

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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.

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Retinal ganglion cell-specific genetic regulation in primary open angle glaucoma

Cited by 3 publications

References 99 publications

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

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

Village in a dish: a model system for population-scale hiPSC studies

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

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