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

Published version
Peer-reviewed

Type

Article

Change log

Authors

Fitzgerald, Tomas W 
UK Biobank Eye and Vision Consortium 

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.

Description

Funder: EMBL


Funder: Alcon Young Investigator Award


Funder: UKRI Future Leaders Fellowship

Keywords

Humans, Rare Diseases, Genome-Wide Association Study, Retina, Photoreceptor Cells, Genetic Variation

Journal Title

PLoS Genet

Conference Name

Journal ISSN

1553-7390
1553-7404

Volume Title

19

Publisher

Public Library of Science (PLoS)
Sponsorship
Wellcome Trust (206619/Z/17/Z)
Medical Research Council (MR/T040912/1)
Novo Nordisk Foundation (NNF17OC0027594 and NNF14CC0001)