Dataset Information

Association of high myopia with crystallin beta A4 (CRYBA4) gene polymorphisms in the linkage-identified MYP6 locus.

ABSTRACT: BACKGROUND: Myopia is the most common ocular disorder worldwide and imposes tremendous burden on the society. It is a complex disease. The MYP6 locus at 22 q12 is of particular interest because many studies have detected linkage signals at this interval. The MYP6 locus is likely to contain susceptibility gene(s) for myopia, but none has yet been identified. METHODOLOGY/PRINCIPAL FINDINGS: Two independent subject groups of southern Chinese in Hong Kong participated in the study an initial study using a discovery sample set of 342 cases and 342 controls, and a follow-up study using a replication sample set of 316 cases and 313 controls. Cases with high myopia were defined by spherical equivalent ? -8 dioptres and emmetropic controls by spherical equivalent within ±1.00 dioptre for both eyes. Manual candidate gene selection from the MYP6 locus was supported by objective in silico prioritization. DNA samples of discovery sample set were genotyped for 178 tagging single nucleotide polymorphisms (SNPs) from 26 genes. For replication, 25 SNPs (tagging or located at predicted transcription factor or microRNA binding sites) from 4 genes were subsequently examined using the replication sample set. Fisher P value was calculated for all SNPs and overall association results were summarized by meta-analysis. Based on initial and replication studies, rs2009066 located in the crystallin beta A4 (CRYBA4) gene was identified to be the most significantly associated with high myopia (initial study: P?=?0.02; replication study: P?=?1.88e-4; meta-analysis: P?=?1.54e-5) among all the SNPs tested. The association result survived correction for multiple comparisons. Under the allelic genetic model for the combined sample set, the odds ratio of the minor allele G was 1.41 (95% confidence intervals, 1.21-1.64). CONCLUSIONS/SIGNIFICANCE: A novel susceptibility gene (CRYBA4) was discovered for high myopia. Our study also signified the potential importance of appropriate gene prioritization in candidate selection.

SUBMITTER: Ho DW

PROVIDER: S-EPMC3389832 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Association of high myopia with crystallin beta A4 (CRYBA4) gene polymorphisms in the linkage-identified MYP6 locus.

Ho Daniel W H DW Yap Maurice K H MK Ng Po Wah PW Fung Wai Yan WY Yip Shea Ping SP

PloS one 20120629 6

<h4>Background</h4>Myopia is the most common ocular disorder worldwide and imposes tremendous burden on the society. It is a complex disease. The MYP6 locus at 22 q12 is of particular interest because many studies have detected linkage signals at this interval. The MYP6 locus is likely to contain susceptibility gene(s) for myopia, but none has yet been identified.<h4>Methodology/principal findings</h4>Two independent subject groups of southern Chinese in Hong Kong participated in the study an in ...[more]

PMID: 22792142

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Project description:PURPOSE: To test the association between myocilin gene (MYOC) polymorphisms and high myopia in Hong Kong Chinese by using family-based association study. METHODS: A total of 162 Chinese nuclear families, consisting of 557 members, were recruited from an optometry clinic. Each family had two parents and at least one offspring with high myopia (defined as -6.00D or less for both eyes). All offspring were healthy with no clinical evidence of syndromic disease and other ocular abnormality. Genotyping was performed for two MYOC microsatellites (NGA17 and NGA19) and five tag single nucleotide polymorphisms (SNPs) spreading across the gene. The genotype data were analyzed with Family-Based Association Test (FBAT) software to check linkage and association between the genetic markers and myopia, and with GenAssoc to generate case and pseudocontrol subjects for investigating main effects of genetic markers and calculating the genotype relative risks (GRR). RESULTS: FBAT analysis showed linkage and association with high myopia for two microsatellites and two SNPs under one to three genetic models after correction for multiple comparisons by false discovery rate. NGA17 at the promoter was significant under an additive model (p=0.0084), while NGA19 at the 3' flanking region showed significant results under both additive (p=0.0172) and dominant (p=0.0053) models. SNP rs2421853 (C>T) exhibited both linkage and association under additive (p=0.0009) and dominant/recessive (p=0.0041) models. SNP rs235858 (T>C) was also significant under additive (p=4.0E-6) and dominant/recessive (p=2.5E-5) models. Both SNPs were downstream of NGA19 at the 3' flanking region. Positive results for these SNPs were novel findings. A stepwise conditional logistic regression analysis of the case-pseudocontrol dataset generated by GenAssoc from the families showed that both SNPs could separately account for the association of NGA17 or NGA19, and that both SNPs contributed separate main effects to high myopia. For rs2421853 and with C/C as the reference genotype, the GRR increased from 1.678 for G/A to 2.738 for A/A (p=9.0E-4, global Wald test). For rs235858 and with G/G as the reference, the GRR increased 2.083 for G/A to 3.931 for A/A (p=2.0E-2, global Wald test). GRR estimates thus suggested an additive model for both SNPs, which was consistent with the finding that, of the three models tested, the additive model gave the lowest p values in FBAT analysis. CONCLUSIONS: Linkage and association was shown between the MYOC polymorphisms and high myopia in our family-based association study. The SNP rs235858 at the 3' flanking region showed the highest degree of confidence for association.

Project description:In order to provide a cost-effective method to narrow down the number of pathogenic Crystallin beta A4 (CRYBA4) non-synonymous single nucleotide polymorphisms (nsSNPs), we collected nsSNP information of the CRYBA4 gene from SNP databases and literature, predicting the pathogenicity and possible changes of protein properties and structures using multiple bioinformatics tools. The nsSNP data of the CRYBA4 gene were collected from 4 databases and published literature. According to 12 criteria, six bioinformatics tools were chosen to predict the pathogenicity. I-Mutant 2.0, Mupro and INPS online tools were used to analyze the effects of amino acid substitution on protein stability by calculating the value of ΔΔG. ConSurf, SOPMA, GETAREA and HOPE online tools were used to predict the evolutionary conservation of amino acids, solvent accessible surface areas, and the physical and chemical properties and changes of protein structure. All 157 CRYBA4 nsSNPs were analyzed. Forty-four CRYBA4 high-risk pathogenic nsSNPs (predicted to be pathogenic by all six software tools) were detected out of the 157 CRYBA4 nsSNPs, four of which (c.283C>T, p.R95W; c.449T>A, p.V150D; c.475G>A, p.G159R; c.575G>C, p.R192P) should be focused on because of their high potential pathogenicity and possibility of changing protein properties. Thirty high-risk nsSNPs were predicted to cause a decrease of protein stability. Twenty-nine high-risk nsSNPs occurred in evolutionary conserved positions. Twenty-two high-risk nsSNPs occurred in the core of the protein. It is predicted that these high-risk pathogenic nsSNPs can cause changes in the physical and chemical properties of amino acids, resulting in structural changes of proteins and changes in the interactions between domains and other molecules, thus affecting the function of proteins. This study provides important reference value when narrowing down the number of pathogenic CRYBA4 nsSNPs and studying the pathogenesis of congenital cataracts. By using this method, we can easily find 44 high-risk pathogenic nsSNPs out of 157 CRYBA4 nsSNPs.

Dataset Information

Association of high myopia with crystallin beta A4 (CRYBA4) gene polymorphisms in the linkage-identified MYP6 locus.

Publications

Association of high myopia with crystallin beta A4 (CRYBA4) gene polymorphisms in the linkage-identified MYP6 locus.

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