Risk Stratification and Clinical Utility of Polygenic Risk Scores in Ophthalmology

Abstract

Combining genetic and clinical data into an informative risk prediction profile has been an important ambition of personalized medicine. Single-nucleotide polymorphisms are commonly found throughout the genome and account for the majority of interindividual genetic variation. To date, genome-wide association studies have led to the discovery of thousands of disease-associated loci, including across dozens of ophthalmic diseases and traits. However, compared with the clinical utility of identifying rare Mendelian variants, the translation of these results to clinical practice has so far been limited because such variants are found commonly in the population, and individually account for a very small risk. Recently, combining large numbers of these genetic variants into polygenic risk scores (PRS) has shown clinically meaningful risk prediction across several common diseases. PRS have the potential to translate the discovery of common risk variants into individualized disease risk prediction, prognostication, and may enable targeted treatments. In this context, we review the clinical utility of PRS in three common, genetically complex ophthalmic conditions: primary open angle glaucoma, age-related macular degeneration, and myopia.Translational Relevance: Common genetic variants can be used to effectively stratify the risk of disease development and progression and may be used to guide screening, triaging, monitoring, or treatment thresholds.

Alcohol, Intraocular Pressure, and Open-Angle Glaucoma

“…Large-scale observational studies and newer genetic epidemiological techniques also offer potential avenues for further investigation, including the use of genetic proxies of alcohol consumption (Mendelian randomization), 101 objective structural glaucoma biomarkers (including inner retinal OCT measures and cup-disc ratios), and polygenic risk scores. 102 As the global burden of glaucoma is projected to increase further over the coming decades, ongoing investigation into environmental risk factors, as well as gene–environment interactions, is necessary to improve our understanding of glaucoma pathogenesis and potentially lead to novel preventative measures and treatment strategies.…”

Genetic Aspects of Age-Related Macular Degeneration and Their Therapeutic Potential

“…The possibility to anticipate the risk of AMD onset would be a major step in the direction of personalised medicine, enabling preventive measures to be implemented in the case of high-risk assets and the development of therapies based on individual genetic structure. A polygenic risk score (PRS) is the sum of the chances to develop a given trait based on genetic susceptibility [ 128 ]. Each variant is weighted according to its size of impact on the disease [ 129 ].…”

Transferability of the PRS estimates for height and BMI obtained from the European ethnic groups to the Western Russian populations

“…It is worth noting that recapitulation of predictive results does not lead to recapitulation of the PRS distribution across the whole population ( Duncan et al, 2019 ). Therefore, the PRS distribution for individual strata for risk management must still be assessed separately ( Qassim et al, 2021 ).…”