Association between ZIC2, RASGRF1, and SHISA6 genes and high myopia in Japanese subjects

We investigated the association of genetic variations, which were identified recently in a large-scale genome-wide association study (GWAS) to confer risk of refractive error and common myopia in Caucasians, with high myopia in Japanese subjects.

The 5 single-nucleotide polymorphisms (SNPs) from the 5 genes TOX, RDH5, ZIC2, RASGRF1, and SHISA6, were genotyped in 1339 unrelated highly myopic Japanese patients and 3248 healthy Japanese participants in the Nagahama Study. In addition, genotypes were compared between high myopia patients without choroidal neovascularization (CNV) and patients with myopic CNV.

Significant associations between rs8000973 near ZIC2 (P = 7.16 × 10(-7)), rs4778879 in RASGRF1 (P = 3.40 × 10(-7)), and rs2969180 in SHISA6 (P = 0.033) and high myopia were observed. Odds ratios (95% confidence intervals) were 1.33 (1.19-1.49), 0.78 (0.71-0.86), and 1.11 (1.01-1.22) for the rs8000973 C allele, rs4778879 A allele, and rs2969180 G allele, respectively. The effect of the rs2969180 allele G contrasted with that observed in the original report, whereas the effect of the other 2 SNPs agreed. Further analysis using controls with -1.0 diopter (D) ≤ spherical equivalent ≤ +1.0 D showed a significant association between ZIC2 and RASGRF1, but not SHISA6. Among the patients with high myopia, 516 had myopic CNV in either eye, while 823 patients did not have myopic CNV in eyes. No evaluated genes showed a significant association with the development of myopic CNV.

ZIC2 and RASGRF1 are susceptibility genes, not only for common myopia, but also for high myopia.