June 2013
Volume 54, Issue 15
Free
ARVO Annual Meeting Abstract  |   June 2013
The Consortium for Refractive Error and Myopia (CREAM) Identifies Four New Loci for Ocular Axial Length and Demonstrates Shared Loci for Axial Length and Refractive Error through Genome-Wide Association Studies
Author Affiliations & Notes
  • Ching-Yu Cheng
    Department of Ophthalmology, National University of Singapore and National University Health System, Singapore, Singapore
    Singapore Eye Research Institute, Singapore, Singapore
  • Maria Schache
    Ocular Genetics Unit, Centre for Eye Research Australia, University of Melbourne, Royal Victorian Eye and Ear Hospital, Melbourne, VIC, Australia
  • Mohammad Ikram
    Department of Ophthalmology, National University of Singapore and National University Health System, Singapore, Singapore
    Singapore Eye Research Institute, Singapore, Singapore
  • Jeremy Guggenheim
    Centre for Myopia Research, School of Optometry, The Hong Kong Polytechnic University, Hong Kong, Hong Kong
  • Dwight Stambolian
    Department of Ophthalmology, University of Pennsylvania, Philadelphia, PA
  • Caroline Klaver
    Department of Ophthalmology, Erasmus Medical Center, Rotterdam, Netherlands
    Department of Epidemiology, Erasmus Medical Center, Rotterdam, Netherlands
  • Yik-Ying Teo
    Saw Swee Hock School of Public Health, National University of Singapore, Singapore, Singapore
    Department of Statistics and Applied Probability, National University of Singapore, Singapore, Singapore
  • Seang-Mei Saw
    Department of Ophthalmology, National University of Singapore and National University Health System, Singapore, Singapore
    Saw Swee Hock School of Public Health, National University of Singapore, Singapore, Singapore
  • Paul Baird
    Ocular Genetics Unit, Centre for Eye Research Australia, University of Melbourne, Royal Victorian Eye and Ear Hospital, Melbourne, VIC, Australia
    Department of Ophthalmology, Centre for Eye Research Australia, University of Melbourne, Royal Victorian Eye and Ear Hospital, Melbourne, VIC, Australia
  • Footnotes
    Commercial Relationships Ching-Yu Cheng, None; Maria Schache, None; Mohammad Ikram, None; Jeremy Guggenheim, None; Dwight Stambolian, None; Caroline Klaver, Bayer (F), Novartis (F), Topcon (F); Yik-Ying Teo, None; Seang-Mei Saw, None; Paul Baird, None
  • Footnotes
    Support None
Investigative Ophthalmology & Visual Science June 2013, Vol.54, 1733. doi:
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      Ching-Yu Cheng, Maria Schache, Mohammad Ikram, Jeremy Guggenheim, Dwight Stambolian, Caroline Klaver, Yik-Ying Teo, Seang-Mei Saw, Paul Baird, CREAM Study Group; The Consortium for Refractive Error and Myopia (CREAM) Identifies Four New Loci for Ocular Axial Length and Demonstrates Shared Loci for Axial Length and Refractive Error through Genome-Wide Association Studies. Invest. Ophthalmol. Vis. Sci. 2013;54(15):1733.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose: To identify genetic variants influencing ocular axial length (AL) through a large-scale meta-analysis of genome-wide association studies (GWAS).

Methods: The Consortium for Refractive Error and Myopia (CREAM) conducted the largest international GWAS meta-analysis of AL, combining 14,287 Caucasians and 8,358 Asians in 18 cohorts from Europe, Australia and Asia. AL was measured using either optical laser interferometry or A-scan ultrasound biometry. Refraction was measured by auto-refractor and/or subjective refraction. Spherical equivalent was calculated as the sphere plus half of the cylinder. Study individuals were genotyped using either Illumina or Affymetrix platforms. Each study performed SNP imputation using the genotyped data, together with HapMap Phase II ethnically matched reference panels. Identified genes were screened for ocular tissue expression in experimental myopic mouse models and human eyes.

Results: A total of six loci influencing AL at genome-wide significance level (P < 5 x 10-8) were identified. Four of these loci are novel, including RSPO1 (rs4074961, P = 3.97 x 10-13), C3orf26 (rs9811920, P = 4.85 x 10-11), LAMA2 (rs12193446, P = 1.24 x 10-8) and ZNRF3 (rs12321, P = 4.08 x 10-8). We also confirmed the AL locus at 1q41 previously identified in Asian populations (ZC3H11B, rs994767; P = 9.62 x 10-12) and the known locus associated with myopia at 15q14 locus (GJD2, rs11073058, P = 4.34 x 10-11). Furthermore, we assessed the effect of these loci on spherical equivalent in 17 independent cohorts comprised of 21,897 individuals through the CREAM. Significant associations (P < 0.05) were identified for GJD2 (rs11073058, P =1.66 x 10-8), LAMA2 (rs12193446, P = 3.58 x 10-10), and ZC3H11B (rs994767; P = 0.013). Differential gene expression in ocular tissues was also observed in lens induced myopia mouse experiments and human ocular tissues.

Conclusions: Newly identified genes enhance our understanding of genetic factors of AL and myopia. In particular, two of these genes (RSPO1 and ZNRF3) are involved in the Wnt signaling pathway. Additionally, this study provides direct evidence of shared genes, GJD2, ZC3H11B and LAMA2, influencing both axial length and refraction.

Keywords: 605 myopia • 534 gene mapping • 539 genetics  
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