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Candidate gene and locus analysis of myopia.

ABSTRACT: A previous study has reported evidence of a strong linkage, but no association, between paired box gene 6 (PAX6) and myopia. We attempted to replicate these findings and to conduct a candidate gene and locus evaluation of genetic involvement in common forms of myopia.Samples were collected from 517 individuals in 123 families with a myopic child participating in the Orinda Longitudinal Study of Myopia or the Contact Lens and Myopia Progression Study. Myopia in the proband children was defined as -0.75 D or more and as being present in both meridians on cycloplegic autorefraction (1% tropicamide). Affected status in parents and siblings was determined by survey. After DNA was extracted from buccal mucosal cells and genotyped using assays for microsatellite markers and single nucleotide polymorphisms (SNPs), DNA was analyzed for linkage disequilibrium. Markers on chromosomes 12 and 18 were selected as regions previously associated with pathological myopia. SNPs were also analyzed in genes where their expression pattern or their association with syndromes conveys myopia as part of the phenotype (FGF2, BDNF, COL2A1, COL18A1, and PAX6).The SNP rs1635529 for COL2A1 on 12q13.11 showed highly significant over-transmission to affected individuals (p=0.00007). No SNP for FGF2, BDNF, COL18A1, or PAX6 showed significant over-transmission to affected individuals after correction for multiple comparisons. Markers on chromosome 12 and 18 previously associated with pathological myopia also showed no significant associations with the more common form of myopia in this study.As reported previously by others, PAX6 showed no association with myopia. Associations in the current analysis are suggestive of involvement of COL2A1. Future studies should focus on replication in other samples and in genome-wide approaches.

SUBMITTER: Mutti DO

PROVIDER: S-EPMC2776540 | biostudies-literature | 2007 Jun

REPOSITORIES: biostudies-literature

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Candidate gene and locus analysis of myopia.

Mutti Donald O DO Cooper Margaret E ME O'Brien Sarah S Jones Lisa A LA Marazita Mary L ML Murray Jeffrey C JC Zadnik Karla K

Molecular vision 20070628

<h4>Purpose</h4>A previous study has reported evidence of a strong linkage, but no association, between paired box gene 6 (PAX6) and myopia. We attempted to replicate these findings and to conduct a candidate gene and locus evaluation of genetic involvement in common forms of myopia.<h4>Methods</h4>Samples were collected from 517 individuals in 123 families with a myopic child participating in the Orinda Longitudinal Study of Myopia or the Contact Lens and Myopia Progression Study. Myopia in the ...[more]

PMID: 17653045

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Project description:Background:Fibroblast growth factor 10 (FGF10) is implicated in the growth and development of the eye. Four singles nucleotide polymorphisms (SNPs) in the FGF10 gene (including rs1384449, rs339501, rs12517396 and rs10462070) were found to be associated with extreme myopia (EM, refractive error???-?10.0 diopters) in Japanese and Chinese Taiwan population. This case-control association study was conducted to explore the relationship between these four SNPs and high myopia in a western Chinese population. Methods:A total of 869 high myopia patients (HM, including 485 EM patients) and 899 healthy controls were recruited. These four SNPs were genotyped using the ABI SNaPshot method. Five genetic models (allelic, homozygous, heterozygous, dominant, and recessive) were applied to further evaluate the possible correlation between the SNPs and high myopia. The linkage-disequilibrium block (LD) structure was tested by Haploview Software. Results:In our study, no statistically significant differences were found between HM/EM patients and controls after Bonferroni multiple-correction (P?>?0.05) in the allele frequencies of these four SNPs in the FGF10 gene. We further found that rs12517396AA and rs10462070GG carriers showed a decreased risk of HM/EM compared with rs12517396AC?+?CC and rs10462070GA?+?AA carriers (P?=?0.045, OR?=?0.366; P?=?0.021, OR?=?0.131; P?=?0.03, OR?=?0.341; P?=?0.015, OR?=?0.122; respectively). Additionally, rs12517396AA and rs10462070GG carriers showed the same decreased risk of HM/EM compared with rs12517396CC and rs10462070AA carriers (P?=?0.048, OR?=?0.370; P?=?0.023, OR?=?0.133; P?=?0.032, OR?=?0.346; P?=?0.017, OR?=?0.126). However, these significant associations between rs12517396/rs10462070 and HM/EM disappeared after Bonferroni multiple-correction (P?>?0.05). Conclusion:Our findings indicate that rs12517396 and rs10462070 had marginal association with HM and EM. The other two common polymorphisms in FGF10 unlikely have significant effects in the genetic predisposition to HM/EM in western Chinese population. Further replication studies are needed to validate our findings in both animal models and human genetic epidemiologic studies.

Project description: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.

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Candidate gene and locus analysis of myopia.

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Candidate gene and locus analysis of myopia.

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