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

Harvard University, United States of America
PLoS Genetics (Impact Factor: 8.17). 06/2012; 8(6):e1002753. DOI: 10.1371/journal.pgen.1002753
Source: PubMed

ABSTRACT 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.

  • [Show abstract] [Hide abstract]
    ABSTRACT: Age-related cataract is a leading cause of blindness worldwide, especially in developing countries where access to cataract surgery remains limited. Previous linkage and candidate gene studies suggested genetic influences on age-related nuclear cataract but few genetic markers have been identified thus far. We conducted genome-wide association studies on 4,569 Asians (including 2,369 Malays and 2,200 Indians), and replicated our analysis in 2,481 Chinese from two independent cohorts (1,768 Chinese in Singapore and 803 Chinese in Beijing). We confirmed two genome-wide significant loci for nuclear cataract in the combined meta-analysis of four cohorts (n=7,140). The first locus was at chromosome 3q25.31 in KCNAB1 (rs7615568, fixed-effect Pmeta=2.30 x 10(-8); random-effect Pmeta=1.08 x 10(-8)). The second locus was at chromosome 21 in the proximity of CRYAA (rs11911275, fixed-effect Pmeta=2.77×10(-8); random-effect Pmeta=1.98 x 10(-9)), a major protein component of eye lens. The findings were further supported by up-regulation and down-regulation of KCNAB1 and CRYAA in human lens capsule, respectively, as the severity of nuclear cataract increases. The results offer additional insights into the pathogenesis of nuclear cataract in Asians.
    Human Molecular Genetics 06/2014; DOI:10.1093/hmg/ddu315 · 6.68 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Corneal curvature measures the steepness of the cornea and is an important parameter for clinically diseases such as astigmatism and myopia. Despite the high heritability of corneal curvature, only two associated genes have been discovered to date. We performed a three-stage genome-wide association study meta-analysis in 12,660 Asian individuals. Our Stage 1 was done in multi-ethnic cohorts comprising 7,440 individuals, followed by a Stage 2 replication in 2,473 Chinese and Stage 3 in 2,747 Japanese. The SNP array genotype data were imputed up to the 1000 Genomes Project Phase 1 cosmopolitan panel. The SNP association with the radii of corneal curvature was investigated in the linear regression model with the adjustment of age, gender, and principal components. In addition to the known genes, MTOR (also known as FRAP1) and PDGFRA, we discovered two novel genes associated with corneal curvature: CMPK1 (rs17103186, P=3.3 x 10(-12)) and RBP3 (rs11204213 [Val884Met], P=1.1 x 10(-13)). The missense RBP3 SNP, rs11204213, was also associated with axial length (P=4.2 x 10(-6)) and had larger effects on both corneal curvature and axial length compared to other SNPs. The index SNPs at the four indicated loci explained 1.9% of corneal curvature variance across the Stages 1 and 2 cohorts, while 33.8% of corneal curvature variance was explained by the genome-wide imputation data. We identified two novel genes influencing corneal curvature, which are related to either corneal shape or eye size. This study provides additional insights into genetic architecture of corneal shape.
    Human Molecular Genetics 06/2014; DOI:10.1093/hmg/ddu322 · 6.68 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Purpose: The immediate early gene Egr-1 is thought to form part of the pathway that mediates abnormal ocular growth. This study investigated whether the mRNA expression levels of Egr-1 in a mammalian retina are modulated differentially, depending on the direction of ocular growth. Methods: To induce accelerated growth and myopia, guinea pigs wore a -5D lens over one eye from 4-11 days of age. To induce inhibited growth, the lens was removed after 7 days of -5D lens wear, and the eye allowed to recover from myopia for 3 days. Ocular parameters and Egr-1 mRNA levels were subsequently assessed. Results: Ocular compensation to a -5 D lens occurred after 7 days (Δ -4.8 D, Δ +147 µm growth, N = 20). In 5 highly myopic eyes (Δ -7.4 D), Egr-1 mRNA levels in the retina were significantly down-regulated relative to contralateral control (51%) and age-matched untreated (47%) eyes. Three days after the -5D lens was removed, eyes had recovered from the myopia (Δ -0.5 D, relative change of +2.9 D, N = 4) and Egr-1 mRNA levels were significantly elevated relative to contralateral (212%) and untreated eyes (234%) respectively. Immunolabelling showed strong Egr-1 reactivity in cell bodies in the inner nuclear and ganglion cell layers. Conclusions: Egr-1 mRNA levels in a mammalian retina show a bi-directional persistent response to opposing ocular growth stimuli. This suggests retinal Egr-1 might act as a signal for the direction of ocular growth in different species.
    Investigative Ophthalmology &amp Visual Science 07/2014; 55(9). DOI:10.1167/iovs.13-11708 · 3.66 Impact Factor

Full-text (2 Sources)

Available from
May 22, 2014