Genetic Variants on Chromosome 1q41 Influence Ocular Axial Length and High Myopia

Harvard University, United States of America
PLoS Genetics (Impact Factor: 7.53). 06/2012; 8(6):e1002753. DOI: 10.1371/journal.pgen.1002753
Source: PubMed


As one of the leading causes of visual impairment and blindness, myopia poses a significant public health burden in Asia. The primary determinant of myopia is an elongated ocular axial length (AL). Here we report a meta-analysis of three genome-wide association studies on AL conducted in 1,860 Chinese adults, 929 Chinese children, and 2,155 Malay adults. We identified a genetic locus on chromosome 1q41 harboring the zinc-finger 11B pseudogene ZC3H11B showing genome-wide significant association with AL variation (rs4373767, β = -0.16 mm per minor allele, P(meta) =2.69 × 10(-10)). The minor C allele of rs4373767 was also observed to significantly associate with decreased susceptibility to high myopia (per-allele odds ratio (OR) =0.75, 95% CI: 0.68-0.84, P(meta) =4.38 × 10(-7)) in 1,118 highly myopic cases and 5,433 controls. ZC3H11B and two neighboring genes SLC30A10 and LYPLAL1 were expressed in the human neural retina, retinal pigment epithelium, and sclera. In an experimental myopia mouse model, we observed significant alterations to gene and protein expression in the retina and sclera of the unilateral induced myopic eyes for the murine genes ZC3H11A, SLC30A10, and LYPLAL1. This supports the likely role of genetic variants at chromosome 1q41 in influencing AL variation and high myopia.

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    • "ted SNPs found in Genome - wide Association Studies ( GWAS ) . Genes Location PM SNP Source GJD2 15q14 rs634990 Solouki et al . 2010 , Nature Genet . RASGRF1 15q25 rs939661 Hysi et al . 2010 , Nature Genet . CTNND2 5q15 rs6885224 , rs12716080 Li et al . 2011 , Ophthalmology MIPEP 13q12 . 12 rs9318086 Shi et al . 2011b , AJHG ZC3H11B 1q41 rs4373767 Fan et al . 2012 , PloS Genetics LAMA2 6q22 . 33 rs12193446 CD55 1q32 . 2 rs1572275 ZNF644 1p22 . 2 rs6680123 Shi et al . 2011a , Plos Genetics MYP11 4q25 rs10034228 , rs1585471 Li et al . 2011 , Hum Mol Genet . BLID 11q24 . 1 rs577948 Nakanishi et al . 2009 , Plos Genetics GLULP3 rs12275397 doi : 10 . 1371"
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    ABSTRACT: Pathological myopia is one of the leading causes of blindness worldwide. The condition is particularly prevalent in Asia. Unlike myopia, pathological myopia is accompanied by degenerative changes in the retina, which if left untreated can lead to irrecoverable vision loss. The accurate diagnosis of pathological myopia will enable timely intervention and facilitate better disease management to slow down the progression of the disease. Current methods of assessment typically consider only one type of data, such as that from retinal imaging. However, different kinds of data, including that of genetic, demographic and clinical information, may contain different and independent information, which can provide different perspectives on the visually observable, genetic or environmental mechanisms for the disease. The combination of these potentially complementary pieces of information can enhance the understanding of the disease, providing a holistic appreciation of the multiple risks factors as well as improving the detection outcomes. In this study, we propose a computer-aided diagnosis framework for Pathological Myopia diagnosis through Biomedical and Image Informatics(PM-BMII). Through the use of multiple kernel learning (MKL) methods, PM-BMII intelligently fuses heterogeneous biomedical information to improve the accuracy of disease diagnosis. Data from 2,258 subjects of a population-based study, in which demographic and clinical information, retinal fundus imaging data and genotyping data were collected, are used to evaluate the proposed framework. The experimental results show that PM-BMII achieves an AUC of 0.888, outperforming the detection results from the use of demographic and clinical information 0.607 (increase , ), genotyping data 0.774 (increase , ) or imaging data 0.852 (increase , ) alone. The accuracy of the results obtained demonstrates the feasibility of using heterogeneous data for improved disease diagnosis through our proposed PM-BMII framework.
    PLoS ONE 06/2013; 8(6):e65736. DOI:10.1371/journal.pone.0065736 · 3.23 Impact Factor
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    • "Recently, several loci, including 11q24.1 (Nakanishi et al. 2009), 15q14 (Solouki et al. 2010), 15q25 (Hysi et al. 2010), 4q25 (Li et al. 2011), 13q12.12 (Shi et al. 2011b), and 1q41 (Fan et al. 2012), have been identified by genome-wide association studies (GWAS) in chromosomal regions associated with complex myopia. Furthermore, other loci were identified by genome-wide meta-analyses (Shi et al. 2013; Stambolian et al. 2013; Verhoeven et al. 2013). "
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    ABSTRACT: Myopia is a refractive error of the eye that is prevalent worldwide. The most extreme form, high myopia, is usually associated with other ocular disorders such as retinal detachment, macular degeneration, cataract, and glaucoma, and is one of leading causes of blindness. The etiology is complex and has not been fully elucidated. In this study, we identified a novel missense variant of the CCDC111 gene (NM_152683.2: c.265T > G; p.Y89D) in a high myopia family by exome sequencing. The variant was identified in 4 patients from an additional 270 sporadic high myopia patients, but not found in 270 controls. The amino acid is highly conserved across species, and variants giving rise to amino acid substitutions are predicted to be functionally damaging. The CCDC111 gene was ubiquitously expressed in primary cell cultures from human eye tissue, including corneal epithelial cells, choroidal melanoma cells, scleral fibroblasts, retinal epithelial cells, retinal Müller cells, and lens capsule epithelial cells. In summary, our results suggested that the CCDC111 may be a susceptibility gene for high myopia.
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