Meta-analysis of Genome-wide Association Studies Identifies a Genetic Locus Influencing Ocular Axial Length and High Myopia in Asian

Abstract

Purpose: : As one of the leading causes of visual impairment, myopia poses a significant burden to public health in Asia. The primary determinant of myopia is the elongated ocular axial length (AL). Although AL is a highly heritable trait, no associated genes have yet been identified.

Methods: : We conducted a meta-analysis of three genome-wide association studies (GWAS) on half million single nucleotide polymorphisms (SNPs) for quantitative trait of AL in 1,860 Chinese adults, 929 Chinese children and 2,155 Malay adults respectively. Moreover, we evaluated these identified SNPs in high myopia predisposition in these three population-based cohorts, along with two additional Japan case-controls studies across a total of 1,118 high myopes and 5,433 non-myopic controls. High myopes are defined as individuals with spherical equivalence ≤ - 9.0 diopters or AL ≥ 28 millimeter. We further examined the expression of the potential candidate genes at this locus in human ocular tissue and myopia-induced mouse model using quantitative Real-Time PCR (qRT-PCR) and immunohistochemistry.

Results: : We identified a region on chromosome 1 to harbor variants that are associated with AL variation (most Significant SNP: meta-P = 2.69 × 10^-10) in the meta-analysis of three GWAS. Further validation in two independent Japanese studies consequently established the role of the same variants in high myopia predisposition (allelic OR = 0.75, 95% CI: 0.68 - 0.84, meta-P = 4.38 x 10^-7). The zinc-finger pesudogene at this locus and two neighboring genes are highly expressed in the human neural retina, retinal pigment epithelium (RPE) and sclera. By inducing myopia in only one eye in a mouse model, we observed significant alterations to mRNA and protein expression in the retina and sclera of myopic eyes across these three murine genes.

Conclusions: : Our findings suggest the likely role of these genetic variants in influencing both AL variation and the susceptibility to high myopia.

Keywords: myopia • gene mapping • genetics