ExGRS: exome-wide genetic risk score to predict high myopia across multi-ancestry populations

Abstract

High myopia (HM), characterized by severe myopic refractive error, stands as a leading cause to visual impairment and blindness globally. HM is a multifactorial ocular disease and presents high heterogeneity in genetics. Employing a genetic risk score (GRS) is useful for capturing genetic susceptibility to HM. Incorporating rare variations into GRS assessment, though presents methodological challenges, yields significant benefits. This study enrolled two independent cohorts: 12,000 unrelated individuals of Han Chinese ancestry from Myopia Associated Genetics and Intervention Consortium (MAGIC) and 8,682 individuals of European ancestry from UK Biobank (UKB). Using whole-exome sequencing (WES) data, we first estimated 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. In the MAGIC cohort, rare variants in low linkage disequilibrium (LD) with neighboring variants were enriched for heritability, particularly for rare deleterious protein-altering variants. Thus, we generated, optimized and validated 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 HM. Individuals with a top 5% ExGRS conffered 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 and 2.03 times (95%CI, 1.65-2.49) higher risk in UKB. Our study implies that rare variants are a major source of the missing heritability of HM in Han Chinese ancestry. And ExGRS provides an enhanced accuracy for HM prediction, shedding new light on research and clinical practice.