A study published in PLOS Genetics presented the largest genome-wide association study (GWAS) of photoreceptor cell (PRC) morphology using quantitative phenotypes taken from optical coherence tomography (OCT) images within the UK Biobank.
What is the UK Biobank?
The UK Biobank is a large-scale biomedical database and resource composed of genetic and health information on around 500,000 United Kingdom patients recruited through the National Health Service (NHS) registry. The database is accessible to researchers across the globe approved to investigate common and life-threatening diseases.
Talk about the study.
Researchers conducted three GWAS—measuring the thickness of each component PRC layer across the respective fields (foveal, intermediate, peripheral)—and averaged this data across the Early Treatment Diabetic Retinopathy (ETDRS) grid for both the left and right eyes. A GWAS was then performed for each of these phenotypes.
Investigators also performed gene burden testing using the UK Biobank 200,000 whole exome release to identify genes that showed an increased level of rare loss of function (LoF) or rare missense variants that were predicted as deleterious and likely damaging.
Results?
Researchers identified 111 loci significantly associated with the thickness of one or more of the PRC layers; of that number, 17 loci overlapped with a known rare retinal disease locus.
Further, 27 genetic variants were found to be associated with PRC thickness, but had no prior associations to ocular or general phenotypes.
Another 10 genes associated with PRC thickness were identified using gene burden testing from exome data, suggesting that the effect of these genetic variants on certain areas of the macula is large enough to impact the average thickness of the PRC layers.
Any limitations?
The authors noted that the results within the GWAS have yet to be replicated using an independent dataset, primarily due to the lack of a comparable dataset with coupled genotypic data and quantitative measures of PRC morphology.
They were also unable to differentiate between compound heterozygotes within the exome data.
They suggested that future work on the study should include exome data analysis at a finer resolution in order to enable genetic discovery.
Significance?
This link between PRC morphology and rare inherited retinal disease offers the possibility of using OCT-derived measures as biomarkers for complex diseases in the future.
The study authors noted that “being able to make these connections between disease phenotypes and genetic variation will open many new opportunities for modern disease diagnosis and therapeutics.”