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Common and rare variation both contribute to the onset of retinal disease

A study published in PLOS Genetics has revealed newly identified risk loci that are associated with rare eye conditions. Using optical images and genetic data from UK Biobank, the team uncovered a variety of common and rare variation associated with photoreceptor thickness.

Uncovering the layers

Diseases that impact one’s eyesight can be debilitating, both on an emotional and physical level. Retinal dystrophies, specifically, are the leading cause of blindness in the non-elderly. These conditions are often caused by mutations in cells known as photoreceptors (PRCs). PRCs detect light in the retina and covert this to an electrical signal, which the brain to turns into images. PRCs are found in layers within the retina, the thickness and morphology of which are associated with the risk of retinal dystrophies and other diseases. The thickness of PRC layers can be examined through optical coherence topography (OCT) – a form of imaging routinely carried out by opticians. An example of an OCT image can be seen in Figure 1.

Figure 1: An example of an optical coherence topography image. The coloured layers represent the different layers of photoreceptors within the retina, allowing for a measurement of thickness. Adapted from Currant et al., 2023.

To examine the link between PRC mutations and retinal diseases, the team of researchers from the European Molecular Biology Laboratory analysed OCT images and genetic data stored in the UK Biobank for over 30,000 individuals. The study is the largest of its kind thus far.

Seeing the full picture

The researchers carried out genome-wide association studies (GWAS) of PRC thickness using the UK Biobank data. The first stage of the work involved a separate GWAS for each PRC layer in the retina. A meta-analysis combining the results of these individual studies identified over 100 loci strongly linked with deviations in PRC layer thickness, including 27 novel associations. Many were situated close to other loci previously associated with rare eye conditions, providing a validation of the results.

Despite these impressive findings, it is important to remember that GWASs typically only test for common variation. Given the rare nature of many retinal diseases, the researchers chose to analyse whole exome data stored within the UK Biobank to identify less common variants that wouldn’t be picked up in a traditional GWAS. This led to identification of 10 risk loci, three of which, again, overlapped with previously identified rare eye disease-associated loci. The genes identified had a variety of different functions, including phototransduction and structural integrity. The findings of the study highlight the boundary between common and rare variation, and the importance of investigating both.

A vision for the future

The devastating nature of retinal dystrophies highlights the need for better understanding and more efficient treatments to prevent blindness. Author Omar Mahroo stated: “Systematic bioinformatic analysis of large-scale participant data cohorts is driving the future of genomic medicine. Having access to these data and being able to make these connections between disease phenotypes and genetic variation will open many new opportunities for modern disease diagnosis and therapeutics.” The work also highlights the integral role of the UK Biobank in health research. First author Hannah Currant remarked: “Access to this enormous amount of data was critical to the study and enabled us to identify genetic links to rare retinal dystrophies. This work has identified new avenues for research and generated new questions about rare retinal dystrophies.”