Mapping of Myopia Susceptibility Genes Using Population-based Association Studies (Case-control Studies)

Myopia is the most common eye disorder in the world. The prevalence of myopia is up to 80% in some Chinese populations. A refractive error in excess of --6.00 diopters (D) is defined as high myopia, which associates eye blindness complications.;The present case-control study started with recruitment of Chinese subjects who were highly myopic (≤ -8.0 D or worse, n=300) or emmetropic (within +/-0.75 D, n=300). The first genetic association study was a replication study for the myocilin (MYOC) gene and the second study was a separate study exploring candidate genes in the MYP2 region by a DNA pooling approach, followed by confirmation using individual genotyping.;MYOC polymorphisms previously found associated with high myopia in previous studies were genotyped together with other SNPs in strong linkage disequilibrium with the positive markers: two microsatellites and eight single nucleotide polymorphisms (SNPs) in total. Five correlated SNPs at the 3' end of the gene showed significant differences between high myopes and controls under three genetic models tested. The results remained significant after correction for multiple comparisons. The two most significant associations with rs64252356 and rs743994 were further confirmed in our original families.;Previous studies using linkage analysis of highly myopic families identified a myopia locus at chromosome 18p11 -- the MYP2 locus. We selected seven candidate genes from the MYP2 region and examined 62 tag SNPs with a two-stage DNA pooling approach. In the first stage, case and control DNA pools were constructed; allele frequencies of SNPs were then compared across 3 replicates of each pool and across two sets of pools by means of nested analysis of variance. In the second stage, nine promising SNPs (P ≤0.10) were further evaluated by individual genotyping. SNP (rs589318) within the LPIN2 gene was found to be associated with high myopia, and the significance survived correction.;In conclusion, the results of the present study implicated the involvement of 3' polymorphisms of the MYOC gene in the predisposition to high myopia. Moreover, we identified the LPIN2 gene in the MYP2 region to be associated with high myopia by a DNA pooling screening strategy.