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. 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 normal and rare variation which impacts retinal structure, sometimes leading to disease.
Competing Interest Statement
APK has acted as a consultant to Abbvie, Aerie, Google Health, Novartis, Reichert, 547 Santen and Thea.
Funding Statement
HC has received support from EMBL and is supported by Novo Nordisk Foundation (grants NNF17OC0027594 and NNF14CC0001). APK is supported by a UKRI Future Leaders Fellowship and an Alcon Young Investigator Award. TWF and EB are supported by EMBL. OAM is supported by the Wellcome Trust (206619/Z/17/Z).
Author Declarations
I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.
Yes
The details of the IRB/oversight body that provided approval or exemption for the research described are given below:
The UK Biobank study was conducted with the approval of the North-West Research Ethics Committee (ref 06/MRE08/65), in accordance with the principles of the Declaration of Helsinki, and all participants gave written informed consent. The research presented here has been conducted using the UK Biobank Resource under Application Number 2112.
I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.
Yes
I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).
Yes
I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.
Yes
Data Availability
The genetic and phenotypic UK Biobank data are available upon application to the UK Biobank.