Nine loci for ocular axial length identified through genome-wide association studies, including shared loci with refractive error

Abstract

Refractive errors are common eye disorders of public health importance worldwide. Ocular axial length (AL) is the major determinant of refraction and thus of myopia and hyperopia. We conducted a meta-analysis of genome-wide association studies for AL, combining 12,531 Europeans and 8,216 Asians. We identified eight genome-wide significant loci for AL (RSPO1, C3orf26, LAMA2, GJD2, ZNRF3, CD55, MIP, and ALPPL2) and confirmed one previously reported AL locus (ZC3H11B). Of the nine loci, five (LAMA2, GJD2, CD55, ALPPL2, and ZC3H11B) were associated with refraction in 18 independent cohorts (n = 23,591). Differential gene expression was observed for these loci in minus-lens-induced myopia mouse experiments and human ocular tissues. Two of the AL genes, RSPO1 and ZNRF3, are involved in Wnt signaling, a pathway playing a major role in the regulation of eyeball size. This study provides evidence of shared genes between AL and refraction, but importantly also suggests that these traits may have unique pathways.

Figure 1

Summary of Meta-analysis Results for Genome-wide Association to Ocular Axial Length Data of both directly genotyped and imputed SNPs are presented in the Manhattan plot. The y axis represents –log₁₀ p values for association with axial length, and the x axis represents chromosomes and base-pair positions based on human genome build 36. The horizontal red line indicates the genome-wide significance level of p < 5.0 × 10⁻⁸. The horizontal blue line indicates the suggestive significance level of p < 1.0 × 10⁻⁵. The previously described locus for axial length is labeled in black. Other loci reaching genome-wide significance identified from the per-SNP meta-analysis are labeled in red. The genes identified in gene-based tests are labeled in blue.

Figure 2

Regional Association Plots and Recombination Rates of the Loci Associated with Ocular Axial Length Data are shown for association at chromosome (A) 1p34.3 (RSPO1), (B) 1q41 (ZC3H11B), (C) 3q12.1 (C3orf26), (D) 6q22.33 (LAMA2), (E) 15q14 (GJD2), and (F) 22q12.1 (ZNRF3) in the combined meta-analysis. Data of both directly genotyped and imputed SNPs are presented. In each panel, the genotyped SNP with the most significant association is denoted with a purple diamond. The color coding of all other SNPs indicates LD with the lead SNP, estimated by CEU r² from phase II HapMap: red, r² ≥ 0.8; yellow, 0.6 ≤ r² < 0.8; green, 0.4 ≤ r² < 0.6; cyan, 0.2 ≤ r² < 0.4; blue, r² < 0.2; and gray, r² unknown. The left y axis represents –log₁₀ p values for association with axial length, the right y axis represents the recombination rate, estimated from the International HapMap Project, and the x axis represents base-pair positions along the chromosome based on human genome build 36. Gene annotations are taken from the University of California Santa Cruz (UCSC) genome browser. The plots were created with LocusZoom.