June 2015
Volume 56, Issue 7
Free
ARVO Annual Meeting Abstract  |   June 2015
Multiple novel loci for corneal curvature identified through genome-wide association studies: The CREAM Consortium
Author Affiliations & Notes
  • Ching-Yu Cheng
    Ocular Epidemiology Research Group, Singapore Eye Research Institute, Singapore, Singapore
    Duke-NUS Graduate Medical School, Singapore, Singapore
  • Qiao Fan
    Ocular Epidemiology Research Group, Singapore Eye Research Institute, Singapore, Singapore
  • Virginie JM Verhoeven
    Department of Ophthalmology, Erasmus Medical Center, Rotterdam, Netherlands
    Department of Epidemiology, Erasmus Medical Center, Rotterdam, Netherlands
  • Jeremy A Guggenheim
    Centre for Myopia Research, The Hong Kong Polytechnic University, Hong Kong, Hong Kong
  • Joan Bailey-Wilson
    Computational and Statistical Genomics Branch, National Human Genome Research Institute, Baltimore, MD
  • Dwight Stambolian
    Department of Ophthalmology, University of Pennsylvania, Philadelphia, PA
  • Tien Yin Wong
    Duke-NUS Graduate Medical School, Singapore, Singapore
    Singapore National Eye Centre, Singapore, Singapore
  • Caroline C W Klaver
    Department of Ophthalmology, Erasmus Medical Center, Rotterdam, Netherlands
    Department of Epidemiology, Erasmus Medical Center, Rotterdam, Netherlands
  • Paul N Baird
    Ocular Genetics Unit, Centre for Eye Research Australia, Melbourne, VIC, Australia
  • Seang-Mei Saw
    Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore, Singapore
    Myopia Research Group, Singapore Eye Research Institute, Singapore, Singapore
  • Footnotes
    Commercial Relationships Ching-Yu Cheng, None; Qiao Fan, None; Virginie Verhoeven, None; Jeremy Guggenheim, None; Joan Bailey-Wilson, None; Dwight Stambolian, None; Tien Wong, None; Caroline Klaver, None; Paul Baird, None; Seang-Mei Saw, None
  • Footnotes
    Support None
Investigative Ophthalmology & Visual Science June 2015, Vol.56, 4351. doi:
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      Ching-Yu Cheng, Qiao Fan, Virginie JM Verhoeven, Jeremy A Guggenheim, Joan Bailey-Wilson, Dwight Stambolian, Tien Yin Wong, Caroline C W Klaver, Paul N Baird, Seang-Mei Saw, ; Multiple novel loci for corneal curvature identified through genome-wide association studies: The CREAM Consortium. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):4351.

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

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Abstract

Purpose: Corneal curvature is an important clinical endophenotype for corneal astigmatism and refractive error. We aimed to identify genetic variants influencing corneal curvature 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 corneal curvature using a two-stage approach. The discovery stage included 18 European-ancestry cohorts consisting of 28,661 individuals, followed by a replication stage of 14,464 individuals from 12 Asian cohorts. The radius of corneal curvature was measured with an auto-keratometer or IOL master. Study individuals were genotyped using either Illumina or Affymetrix platforms. After stringent quality controls, genotype data in each cohort were imputed to the 1000 Genomes reference panel. The genotype and phenotype association was assessed using linear regression analysis under an additive effect model, adjusting for age, gender and principal components.

Results: We identified a total of 23 loci influencing corneal curvature at the genome-wide significance level (P < 5 x 10-8) in Europeans; of these, 17 were novel and were also replicated in Asians. The combined analysis of all discovery and replication cohorts revealed an additional 19 novel loci for corneal curvature with low cross-cohort heterogeneity. The most significant locus harbors RSPO1 (P = 2.29 x 10-29), a gene previously identified by CREAM as influencing axial length. We also confirmed association with four previously identified corneal curvature loci, including PDGFRA (rs7682912, P = 8.24 x 10-24), FRAP1 (rs3737611, P = 8.16 x 10-23), CMPK1 (rs60078183, P = 4.61 x10-14) and RBP3 (rs11204213, P = 7.94 x10-12). The novel gene loci implicate a number of different pathways but reinforce the likely involvement of cell differentiation and proliferation playing an important role in corneal curvature.

Conclusions: Our study represents the largest multi-ancestry GWAS on corneal curvature, which identified a total of 36 novel loci influencing corneal curvature. The results also provide direct evidence of shared genes, such as RSPO1, that appears to influence both corneal curvature as well as axial length.

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