Identification of Novel Loci Influencing Refractive Error in East Asian Populations Using an Extreme Phenotype Design

Background: Large proportion of genetic heritability for refractive error (RE) is unexplained, and little evidence exist for East Asian populations where the myopia prevalence is significantly higher.  Methods: The discovery stage GWASs and meta-analysis were conducted in 1852 Chinese Han individuals with extreme spherical equivalent (SE) values from Guangzhou (631 0D) and Wenzhou (593 -1·75 D). The replication study was carried out in an independent Chinese cohort of 1053 individuals without preselection on SE (mean SE = -1·97D, sd = 2·49D). An additional gene-based GWAS was conducted based on the meta-analysis results. Findings:  Three novel loci showed genome-wide significant association 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 replicated at nominal significance. The allele frequencies of all three loci showed significant differences between major continental groups (P < 0·001). The SE reducing (more myopic) allele of rs10913877 had the highest frequency in East Asians and much lower frequencies in Europeans and Africans (EAS =0·60, EUR = 0·20, AFR = 0·18), which was largely consistent with the global distribution of myopia. The gene-based analysis additionally identified four novel genes associated with SE, including FAM163A,EI24,  LHX5,ARPP19.  Interpretation: Our study identified three novel loci associated with SE in East Asian populations, and indicated the role of genetic heterogeneity in different myopia prevalence among different ethnicities. Funding: Strategic Priority Research Program of Chinese Academy of Sciences; National Key R&D Program of China. Declaration of Interest: The authors declare that they have no competing interests Ethical Approval: The study was conducted with the approval of the Zhongshan Ophthalmic Center (ZOC) Ethics Committee, and followed the principles of the Declaration of Helsinki. Written informed consent was obtained and signed by each participant. A detailed study methodology had been previously reported (registered as “ISRCTN45213099- Zhongshan Angle-closure Prevention Study,” http://www.controlled-trials.com/ISRCTN45213099). Conduction of this trial followed the tenets of the Declaration of Helsinki, and written informed consent was acquired from all participants.