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

Maciej Daniszewski; Anne Senabouth; Helena H. Liang; Xikun Han; Grace E. Lidgerwood; Damián Hernández; Priyadharshini Sivakumaran; Jordan E. Clarke; Shiang Y. Lim; Jarmon G. Lees; Louise Rooney; Lerna Gulluyan; Emmanuelle Souzeau; Stuart L. Graham; Chia Ling Chan; Uyen Nguyen; Nona Farbehi; Vikkitharan Gnanasambandapillai; Rachael A. McCloy; Linda Clarke; Lisa S. Kearns; David A. Mackey; Jamie E. Craig; Stuart MacGregor; Joseph E. Powell; Alice Pébay; Alex W. Hewitt

doi:10.1016/j.xgen.2022.100142

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

Maciej Daniszewski, Anne Senabouth, Helena H. Liang, Xikun Han, Grace E. Lidgerwood, Damián Hernández, Priyadharshini Sivakumaran, Jordan E. Clarke, Shiang Y. Lim, Jarmon G. Lees, Louise Rooney, Lerna Gulluyan, Emmanuelle Souzeau, Stuart L. Graham, Chia Ling Chan, Uyen Nguyen, Nona Farbehi, Vikkitharan Gnanasambandapillai, Rachael A. McCloy, Linda ClarkeLisa S. Kearns, David A. Mackey, Jamie E. Craig, Stuart MacGregor, Joseph E. Powell^*, Alice Pébay, Alex W. Hewitt

^*Corresponding author for this work

Macquarie Medical School

Research output: Contribution to journal › Article › peer-review

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Abstract

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.

Original language	English
Article number	100142
Pages (from-to)	1-14, e1-e5
Number of pages	20
Journal	Cell Genomics
Volume	2
Issue number	6
DOIs	https://doi.org/10.1016/j.xgen.2022.100142
Publication status	Published - 8 Jun 2022

Bibliographical note

Copyright the Author(s) 2022. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

Keywords

eQTL
glaucoma
human induced pluripotent stem cells
retinal ganglion cells
retinal organoids
single-cell RNA sequencing
transcriptomics

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10.1016/j.xgen.2022.100142Licence: CC BY-NC-ND

Publisher version (open access)Final published version, 4.19 MBLicence: CC BY-NC-ND

Cite this

Daniszewski, M., Senabouth, A., Liang, H. H., Han, X., Lidgerwood, G. E., Hernández, D., Sivakumaran, P., Clarke, J. E., Lim, S. Y., Lees, J. G., Rooney, L., Gulluyan, L., Souzeau, E., Graham, S. L., Chan, C. L., Nguyen, U., Farbehi, N., Gnanasambandapillai, V., McCloy, R. A., ... Hewitt, A. W. (2022). Retinal ganglion cell-specific genetic regulation in primary open-angle glaucoma. Cell Genomics, 2(6), 1-14, e1-e5. Article 100142. https://doi.org/10.1016/j.xgen.2022.100142

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title = "Retinal ganglion cell-specific genetic regulation in primary open-angle glaucoma",

abstract = "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.",

keywords = "eQTL, glaucoma, human induced pluripotent stem cells, retinal ganglion cells, retinal organoids, single-cell RNA sequencing, transcriptomics",

author = "Maciej Daniszewski and Anne Senabouth and Liang, {Helena H.} and Xikun Han and Lidgerwood, {Grace E.} and Dami{\'a}n Hern{\'a}ndez and Priyadharshini Sivakumaran and Clarke, {Jordan E.} and Lim, {Shiang Y.} and Lees, {Jarmon G.} and Louise Rooney and Lerna Gulluyan and Emmanuelle Souzeau and Graham, {Stuart L.} and Chan, {Chia Ling} and Uyen Nguyen and Nona Farbehi and Vikkitharan Gnanasambandapillai and McCloy, {Rachael A.} and Linda Clarke and Kearns, {Lisa S.} and Mackey, {David A.} and Craig, {Jamie E.} and Stuart MacGregor and Powell, {Joseph E.} and Alice P{\'e}bay and Hewitt, {Alex W.}",

note = "Copyright the Author(s) 2022. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.",

year = "2022",

month = jun,

day = "8",

doi = "10.1016/j.xgen.2022.100142",

language = "English",

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Daniszewski, M, Senabouth, A, Liang, HH, Han, X, Lidgerwood, GE, Hernández, D, Sivakumaran, P, Clarke, JE, Lim, SY, Lees, JG, Rooney, L, Gulluyan, L, Souzeau, E, Graham, SL, Chan, CL, Nguyen, U, Farbehi, N, Gnanasambandapillai, V, McCloy, RA, Clarke, L, Kearns, LS, Mackey, DA, Craig, JE, MacGregor, S, Powell, JE, Pébay, A & Hewitt, AW 2022, 'Retinal ganglion cell-specific genetic regulation in primary open-angle glaucoma', Cell Genomics, vol. 2, no. 6, 100142, pp. 1-14, e1-e5. https://doi.org/10.1016/j.xgen.2022.100142

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AU - Daniszewski, Maciej

AU - Senabouth, Anne

AU - Liang, Helena H.

AU - Han, Xikun

AU - Lidgerwood, Grace E.

AU - Hernández, Damián

AU - Sivakumaran, Priyadharshini

AU - Clarke, Jordan E.

AU - Lim, Shiang Y.

AU - Lees, Jarmon G.

AU - Rooney, Louise

AU - Gulluyan, Lerna

AU - Souzeau, Emmanuelle

AU - Graham, Stuart L.

AU - Chan, Chia Ling

AU - Nguyen, Uyen

AU - Farbehi, Nona

AU - Gnanasambandapillai, Vikkitharan

AU - McCloy, Rachael A.

AU - Clarke, Linda

AU - Kearns, Lisa S.

AU - Mackey, David A.

AU - Craig, Jamie E.

AU - MacGregor, Stuart

AU - Powell, Joseph E.

AU - Pébay, Alice

AU - Hewitt, Alex W.

N1 - Copyright the Author(s) 2022. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

PY - 2022/6/8

Y1 - 2022/6/8

N2 - 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.

AB - 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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KW - glaucoma

KW - human induced pluripotent stem cells

KW - retinal ganglion cells

KW - retinal organoids

KW - single-cell RNA sequencing

KW - transcriptomics

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U2 - 10.1016/j.xgen.2022.100142

DO - 10.1016/j.xgen.2022.100142

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SP - 1-14, e1-e5

JO - Cell Genomics

JF - Cell Genomics

IS - 6

M1 - 100142

ER -

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

Abstract

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Keywords

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