Mapping of myopia susceptibility genes using population-based association studies (case-control studies)

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Mapping of myopia susceptibility genes using population-based association studies (case-control studies)

 

Author: Lo, Ka-kin
Title: Mapping of myopia susceptibility genes using population-based association studies (case-control studies)
Degree: Ph.D.
Year: 2011
Subject: Myopia -- Genetic aspects
Hong Kong Polytechnic University -- Dissertations
Department: School of Optometry
Pages: xxii, 339 p. : ill. (some col.) ; 30 cm.
Language: English
InnoPac Record: http://library.polyu.edu.hk/record=b2507186
URI: http://theses.lib.polyu.edu.hk/handle/200/6465
Abstract: Myopia is the most common eye disorder in the world. The prevalence of myopia is up to 30% in western countries, but may be as high as 80% in some Chinese populations. A refractive error in excess of -6.00 diopters (D) is defined as high myopia, also called pathologic myopia because of its associated potential eye complications, which can lead to blindness. The prevalence of high myopia can reach as high as 24% in Chinese populations while it is only up to 5% in western countries. The present case-control study started with recruitment of Chinese subjects who were highly myopic (≤ -6.0 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. Several studies have reported the association of several MYOC polymorphisms with high myopia, including one family-based study from our group. However, other studies reported negative findings. We attempted to replicate previous studies in a case-control study involving 300 cases and 300 controls. MYOC polymorphisms previously found associated with high myopia 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 (genotypic, additive and allelic): rs12076134, rs1602244, rs6425356, rs10737323 and rs743994. The results remained significant after correction for multiple comparisons by false discovery rate at 0.05 levels. The two most significant associations with rs64252356 and rs743994 were further confirmed in our original families. These SNPs have not been investigated by any other groups up to date. Three polymorphisms previously associated with high myopia failed to be replicated, suggesting that the original positive results were probably chance findings. One previously positive SNP failed to be replicated because of local variation in the linkage disequilibrium patterns in the case-control subjects.
Previous studies using linkage analysis of families with highly myopic members identified a myopia locus at chromosome 18p11 the MYP2 locus. We selected seven candidate genes (CLUL1, EMLIN-2, LPIN2, MYOM1, MYL12A, MYL12B and ZFP161) from the MYP2 region and examined 62 tag SNPs with a two-stage DNA pooling approach. In the first stage, 6 case pools and 6 control pools were constructed using DNA samples from 300 high myopes and 300 controls. Each DNA pool was prepared by mixing equal amounts of DNA from 50 distinct subjects of the same affection status. Allele frequencies of SNPs were estimated by analysis of primer-extended products in a denaturing high performance liquid chromatography system, and 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 of samples included in the pools. One SNP (rs589318) within the LPIN2 gene was found to be associated with high myopia under three genetic models (genotypic, additive and allelic), and the significance survived correction by false discovery rate at 0.05 level. This is a novel finding not previously reported. 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 successfully applied a DNA pooling strategy to screen candidate genes in the MYP2 region and identified the LPIN2 gene to be associated with high myopia. These are novel findings and should be replicated using independent sample sets.

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