The vasoactive intestinal peptide receptor 2 (VIPR2) gene, a myopia susceptibility locus, contains variants showing opposite effects

Background and objective: Myopia is the commonest eye disorder worldwide. High myopes are predisposed to ocular pathologies. The VIPR2 gene was identified as a myopia susceptibility locus by our group and another group. We continued to fine-map this locus. Methodology: A case-control study was performed in 4 sequential stages with a total of 941 highly myopic subjects and 846 control subjects, all unrelated individuals of Chinese descent. Stage 1 experimentally genotyped 64.4% of the entire cohort for 152 single-nucleotide polymorphisms (SNPs) and Stage 2 the remaining subjects for 21 SNPs. For genotyping, Stage 1 used custom-made Infinium iSelect BeadChips while Stage 2 employed iPLEX assay and unlabelled probe melting analysis. Stage 3 combined the genotypes for 21 SNPs for the entire cohort for analysis. Stage 4 imputed genotypes for variants in the VIPR2 region. Genetic association was tested using PLINK with multiple-testing correction by permutation. Results: Results of Stage-1 study enabled fewer SNPs to be genotyped in Stage 2. Stage 3 identified one group of high-risk haplotypes and one group of protective haplotypes significantly associated with high myopia. Stage 4 identified two independent groups of associated variants: one group with high-risk minor alleles (odds ratio >1.00) and one group with protective minor alleles (odds ratio <1.00) – results consistent with those of Stage 3. Variants within each group were generally in strong linkage disequilibrium among themselves while high-risk variants were in linkage equilibrium with protective variants. Conclusions: The VIPR2 locus contains variants with opposite effects. To the best of our knowledge, this is the first study that has examined the genetic architecture of a myopia susceptibility locus in detail.