Elsevier

Ophthalmology

Volume 118, Issue 2, February 2011, Pages 368-375
Ophthalmology

Original article
Genome-Wide Association Studies Reveal Genetic Variants in CTNND2 for High Myopia in Singapore Chinese

https://doi.org/10.1016/j.ophtha.2010.06.016Get rights and content

Objective

To determine susceptibility genes for high myopia in Singaporean Chinese.

Design

A meta-analysis of 2 genome-wide association (GWA) datasets in Chinese and a follow-up replication cohort in Japanese.

Participants and Controls

Two independent datasets of Singaporean Chinese individuals aged 10 to 12 years (Singapore Cohort Study of the Risk factors for Myopia [SCORM]: cases = 65, controls = 238) and more than 21 years (Singapore Prospective Study Program [SP2]: cases = 222, controls = 435) for GWA studies, and a Japanese dataset aged more than 20 years (cases = 959, controls = 2128) for replication.

Methods

Genomic DNA samples from SCORM and SP2 were genotyped using various Illumina Beadarray platforms (>HumanHap 500). Single-locus association tests were conducted for each dataset with meta-analysis using pooled z-scores. The top-ranked genetic markers were examined for replication in the Japanese dataset. Fisher P was calculated for the combined analysis of all 3 cohorts.

Main Outcome Measures

High myopia, defined by spherical equivalent (SE)≤−6.00 diopters (D); controls defined by SE between −0.50 and +1.00 D.

Results

Two SNPs (rs12716080 and rs6885224) in the gene CTNND2 on chromosome 5p15 ranked top in the meta-analysis of our Chinese datasets (meta P = 1.14×10−5 and meta P = 1.51×10−5, respectively) with strong supporting evidence in each individual dataset analysis (max P = 1.85×10−4 in SCORM: max P = 8.8×10−3 in SP2). Evidence of replication was observed in the Japanese dataset for rs6885224 (P = 0.035, meta P of 3 datasets: 7.84×10−6).

Conclusions

This study identified a strong association of CTNND2 for high myopia in Asian datasets. The CTNND2 gene maps to a known high myopia linkage region on chromosome 5p15.

Financial Disclosure(s)

Proprietary or commercial disclosure may be found after the references.

Section snippets

Study Populations

The SCORM and SP2 are the primary datasets in this study with genome-wide, high-density SNP data. The SCORM is one of the few cohorts with precise longitudinal ocular phenotypic data from predominantly Chinese Singaporean children.18 The SP2 is a population-based study of primarily Chinese adults aged 21 years or more with refractive error data.19, 20, 21, 22 Our study adhered to the Declaration of Helsinki. The SCORM was approved by the institutional review boards of the National University of

Genome-Wide Association Analysis Datasets

The basic demographic data for both SCORM and SP2 datasets are summarized in Table 1, and the description of SNPs selection process for meta-analysis of both cohorts is shown in Figure 1.

The post-QC SCORM GWA dataset comprised 929 subjects (481 male and 448 female) with refractive error data, of which 65 subjects have high myopia and 238 subjects are emmetropic controls. Because of 2 types of Illumina chips used in SCORM, only 541 849 autosomal SNPs were investigated. We excluded 69 801 markers

Discussion

This study used 2 GWA datasets of Singaporean Chinese with 287 high myopia cases and 693 controls of 2937 GWA samples, and a follow-up replication study in 3087 (959 high myopia cases and 2128 controls) Japanese. Because we combined refractive error data from children and adults, high myopia is likely the more robust phenotype, because children with high myopia are likely to remain highly myopic for life and phenotype reversal is rare.

We found significant association of the CTNND2 gene on

Acknowledgments

The authors thank the following Duke University affiliates: Carol Haynes, AB, for participation in the databasing of genotype data from the SCORM GWA study, Dr. Andrew Dellinger, PhD, for participation in providing initial assistance with the bioinformatics, and Dr. Dana Hornbeak, MD, for participation in generating the initial summary tables for the SCORM GWA study.

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    Manuscript no. 2010-316.

    Financial Disclosure(s): The authors have made the following disclosures: E-Shyong Tai: Consultant, Glaxo-Smith Kline; Consultant, Merck Sharp and Dohme (IA) Corp.

    Funding: The SCORM GWA study is supported by the Singapore BioMedical Research Council, grant 06/1/21/19/466 to SSM and the US National Institutes of Health grant (1R21-EY-019086-01) to YJL. The SP2 GWA study is supported by BioMedical Research Council, grant 03/1/27/18/216 to EST. TLY is supported by research funding from the Duke-NUS Graduate Medical School, and Research to Prevent Blindness, Inc. Additional support was provided by the Singapore Tissue Network. The sponsor or funding organization had no role in the design or conduct of this research.

    These authors contributed equally to the manuscript.

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