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Sub-cellular level resolution of common genetic variation in the photoreceptor layer identifies continuum between rare disease and common variation

Currant, Hannah; Fitzgerald, Tomas W; Patel, Praveen J; Khawaja, Anthony P; UK Biobank Eye and Vision Consortium; Webster, Andrew R; Mahroo, Omar A; (2023) Sub-cellular level resolution of common genetic variation in the photoreceptor layer identifies continuum between rare disease and common variation. PLoS Genetics , 19 (2) , Article e1010587. 10.1371/journal.pgen.1010587. (In press). Green open access

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Abstract

Photoreceptor cells (PRCs) are the light-detecting cells of the retina. Such cells can be non-invasively imaged using optical coherence tomography (OCT) which is used in clinical settings to diagnose and monitor ocular diseases. Here we present the largest genome-wide association study of PRC morphology to date utilising quantitative phenotypes extracted from OCT images within the UK Biobank. We discovered 111 loci associated with the thickness of one or more of the PRC layers, many of which had prior associations to ocular phenotypes and pathologies, and 27 with no prior associations. We further identified 10 genes associated with PRC thickness through gene burden testing using exome data. In both cases there was a significant enrichment for genes involved in rare eye pathologies, in particular retinitis pigmentosa. There was evidence for an interaction effect between common genetic variants, VSX2 involved in eye development and PRPH2 known to be involved in retinal dystrophies. We further identified a number of genetic variants with a differential effect across the macular spatial field. Our results suggest a continuum between common and rare variation which impacts retinal structure, sometimes leading to disease.

Type: Article
Title: Sub-cellular level resolution of common genetic variation in the photoreceptor layer identifies continuum between rare disease and common variation
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1371/journal.pgen.1010587
Publisher version: https://doi.org/10.1371/journal.pgen.1010587
Language: English
Additional information: Copyright: © 2023 Currant et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Keywords: UK Biobank Eye and Vision Consortium
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > Institute of Ophthalmology
URI: https://discovery.ucl.ac.uk/id/eprint/10166120
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