The Consortium for Refractive Error and Myopia (CREAM) Identifies Four New Loci for Ocular Axial Length and Demonstrates Shared Loci for Axial Length and Refractive Error through Genome-Wide Association Studies

Abstract

Purpose: To identify genetic variants influencing ocular axial length (AL) through a large-scale meta-analysis of genome-wide association studies (GWAS).

Methods: The Consortium for Refractive Error and Myopia (CREAM) conducted the largest international GWAS meta-analysis of AL, combining 14,287 Caucasians and 8,358 Asians in 18 cohorts from Europe, Australia and Asia. AL was measured using either optical laser interferometry or A-scan ultrasound biometry. Refraction was measured by auto-refractor and/or subjective refraction. Spherical equivalent was calculated as the sphere plus half of the cylinder. Study individuals were genotyped using either Illumina or Affymetrix platforms. Each study performed SNP imputation using the genotyped data, together with HapMap Phase II ethnically matched reference panels. Identified genes were screened for ocular tissue expression in experimental myopic mouse models and human eyes.

Results: A total of six loci influencing AL at genome-wide significance level (P < 5 x 10^-8) were identified. Four of these loci are novel, including RSPO1 (rs4074961, P = 3.97 x 10^-13), C3orf26 (rs9811920, P = 4.85 x 10^-11), LAMA2 (rs12193446, P = 1.24 x 10^-8) and ZNRF3 (rs12321, P = 4.08 x 10^-8). We also confirmed the AL locus at 1q41 previously identified in Asian populations (ZC3H11B, rs994767; P = 9.62 x 10^-12) and the known locus associated with myopia at 15q14 locus (GJD2, rs11073058, P = 4.34 x 10^-11). Furthermore, we assessed the effect of these loci on spherical equivalent in 17 independent cohorts comprised of 21,897 individuals through the CREAM. Significant associations (P < 0.05) were identified for GJD2 (rs11073058, P =1.66 x 10^-8), LAMA2 (rs12193446, P = 3.58 x 10^-10), and ZC3H11B (rs994767; P = 0.013). Differential gene expression in ocular tissues was also observed in lens induced myopia mouse experiments and human ocular tissues.

Conclusions: Newly identified genes enhance our understanding of genetic factors of AL and myopia. In particular, two of these genes (RSPO1 and ZNRF3) are involved in the Wnt signaling pathway. Additionally, this study provides direct evidence of shared genes, GJD2, ZC3H11B and LAMA2, influencing both axial length and refraction.

Keywords: 605 myopia • 534 gene mapping • 539 genetics