Background: High myopia (HM), characterized by a severe myopic refractive error, stands as a leading cause of visual impairment and blindness globally. HM is a multifactorial ocular disease that presents high genetic heterogeneity. Employing a genetic risk score (GRS) is useful for capturing genetic susceptibility to HM.
Methods: This study assesses the effectiveness of these strategies via incorporating rare variations into the GRS assessment. This study enrolled two independent cohorts: 12,600 unrelated individuals of Han Chinese ancestry from Myopia Associated Genetics and Intervention Consortium (MAGIC) and 8682 individuals of European ancestry from UK Biobank (UKB).
Results: Here, we first estimate the heritability of HM resulting in 0.53 (standard error, 0.06) in the MAGIC cohort and 0.21 (standard error, 0.10) in the UKB cohort by using whole-exome sequencing (WES) data. We generate, optimize, and validate an exome-wide genetic risk score (ExGRS) for HM prediction by combining rare risk genotypes with common variant GRS (cvGRS). ExGRS improved the AUC from 0.819 (cvGRS) to 0.856 for 1219 Han Chinese individuals of an independent testing dataset. Individuals with a top 5% ExGRS confer a 15.57-times (95% CI, 5.70-59.48) higher risk for developing HM compared to the remaining 95% of individuals in MAGIC cohort.
Conclusions: Our study suggests that rare variants are a major source of the missing heritability of HM and that ExGRS provides enhanced accuracy for HM prediction in Han Chinese ancestry, shedding new light on research and clinical practice.
High Myopia (HM) is a disease of the eyes frequently caused by one’s inherited genes. Mathematical equations can be used to predict disease risk based on a person’s genetic make-up (profile). This calculation, called a genetic risk score (GRS), doesn’t include rare genetic changes and it is challenging to consider these in the calculations. Here, we test whether combining rare genetic changes can help to predict HM risk. Our calculations not only outperformed existing methods used for HM risk, they also allow us to estimate an individual’s risk of HM, showing how important including rare genetic changes are in accurately predicting risk of this disorder.
© 2024. The Author(s).