June 2023
Volume 64, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2023
Novel genetic enrichment analyses of single cell RNA sequencing datasets identifies important cell types influencing primary open angle glaucoma and refractive error.
Author Affiliations & Notes
  • Christopher J Hammond
    Ophthalmology, King's College London Faculty of Life Sciences and Medicine, London, London, United Kingdom
    Twin Research & Genetic Epidemiology, King's College London Faculty of Life Sciences and Medicine, London, London, United Kingdom
  • Pirro G Hysi
    Ophthalmology, King's College London Faculty of Life Sciences and Medicine, London, London, United Kingdom
    Twin Research & Genetic Epidemiology, King's College London Faculty of Life Sciences and Medicine, London, London, United Kingdom
  • Footnotes
    Commercial Relationships   Christopher Hammond None; Pirro Hysi None
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science June 2023, Vol.64, 3271. doi:
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      Christopher J Hammond, Pirro G Hysi; Novel genetic enrichment analyses of single cell RNA sequencing datasets identifies important cell types influencing primary open angle glaucoma and refractive error.. Invest. Ophthalmol. Vis. Sci. 2023;64(8):3271.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : Genome-wide association studies (GWAS) have expanded knowledge of the pathogenetic mechanisms underlying eye diseases. Efforts to reconstruct the interactions between genes and pathways are impeded by the complexity of eye tissues which show considerable histological and tissue gene expression heterogeneity. Single-cell RNA sequencing (scRNAseq) is a relatively new technology which may help elucidate the role different structures and cell types play in specific ocular diseases.

Methods : We ran LDscore-based enrichment analyses using libraries of gene expression for each of the cell lines present in the eye and that were successfully characterized through single-cell RNA sequencing (scRNAseq) data. Libraries were built using open access scRNA datasets that had information from at least 5 individual donors. Enrichment analyses were run on GWAS summary statistics for refractive error (N=542,934) and primary open-angle glaucoma (POAG, N=34,179 cases and 349,321 controls).

Results : For POAG-associated genes the strongest enrichment was observed for cells in the juxtacanalicular (JCT) or cribriform region (p=0.001). These cells are the part of the deepest trabecular meshwork tissues adjacent to the inner wall endothelium of Schlemm’s canal. Lamellar beam B cells, found near the ciliary muscle and the trabecular meshwork (TM) uveal base, showed the second most significant enrichment (p=0.003). Interestingly, ciliary body cells (p=0.02) and Schlemm’s canal endothelium (p=0.11) showed little or no enrichment.
Using refractive error GWAS results, strongest enrichments were for genes expressed in cone cells (p=0.0008). Two subpopulations of rod cells the next most enriched (p=0.002 and 0.02 respectively). Other rod cell subpopulations were not significantly enriched.

Conclusions : scRNAseq data is a valuable resource that can cast light on cell and tissue-specific processes in eye diseases. We report a specific area of the TM nearest Schlemm’s canal is the anatomical structure likely to have the strongest influence over POAG; specific photoreceptor subpopulations are likely to play a major role in the development of refractive error. These libraries will be available to researchers for future exploration of molecular mechanisms of other eye diseases.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.

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