Identification of novel loci influencing refractive error in East Asian populations using an extreme phenotype design

The global "myopia boom" has raised significant international concerns. Despite a higher myopia prevalence in Asia, previous large-scale genome-wide association studies (GWASs) were mostly based on European descendants. Here, we report a GWAS of spherical equivalent (SE) in 1852 Chinese Han individuals with extreme SE from Guangzhou (631 0D) and Wenzhou (593 −1.75 D), followed by a replication study in two independent cohorts with totaling 3538 East Asian individuals. The discovery GWAS and meta-analysis identify three novel loci which show genome-wide significant associations with SE, including 1q25.2 FAM163A, 10p11.22 NRP1/PRAD3, and 10p11.21 ANKRD30A/MTRNR2L7, together explaining 3.34% of SE variance. 10p11.21 was successfully replicated. The allele frequencies of all three loci show significant differences between major continental groups (P < 0.001). The SE reducing (more myopic) allele of rs10913877 (1q25.2 FAM163A) demonstrates the highest frequency in East Asians and much lower frequencies in Europeans and Africans (EAS = 0.60, EUR = 0.20, AFR = 0.18). The gene-based analysis additionally identifies three novel genes associated with SE, including EI24, LHX5 and ARPP19. These results provide new insights into myopia pathogenesis, and indicate the role of genetic heterogeneity in myopia epidemiology among different ethnicities.