A genome-wide association study of corneal astigmatism: The CREAM Consortium

Mol Vis. 2018 Feb 5;24:127-142. eCollection 2018.


Purpose: To identify genes and genetic markers associated with corneal astigmatism.

Methods: A meta-analysis of genome-wide association studies (GWASs) of corneal astigmatism undertaken for 14 European ancestry (n=22,250) and 8 Asian ancestry (n=9,120) cohorts was performed by the Consortium for Refractive Error and Myopia. Cases were defined as having >0.75 diopters of corneal astigmatism. Subsequent gene-based and gene-set analyses of the meta-analyzed results of European ancestry cohorts were performed using VEGAS2 and MAGMA software. Additionally, estimates of single nucleotide polymorphism (SNP)-based heritability for corneal and refractive astigmatism and the spherical equivalent were calculated for Europeans using LD score regression.

Results: The meta-analysis of all cohorts identified a genome-wide significant locus near the platelet-derived growth factor receptor alpha (PDGFRA) gene: top SNP: rs7673984, odds ratio=1.12 (95% CI:1.08-1.16), p=5.55×10-9. No other genome-wide significant loci were identified in the combined analysis or European/Asian ancestry-specific analyses. Gene-based analysis identified three novel candidate genes for corneal astigmatism in Europeans-claudin-7 (CLDN7), acid phosphatase 2, lysosomal (ACP2), and TNF alpha-induced protein 8 like 3 (TNFAIP8L3).

Conclusions: In addition to replicating a previously identified genome-wide significant locus for corneal astigmatism near the PDGFRA gene, gene-based analysis identified three novel candidate genes, CLDN7, ACP2, and TNFAIP8L3, that warrant further investigation to understand their role in the pathogenesis of corneal astigmatism. The much lower number of genetic variants and genes demonstrating an association with corneal astigmatism compared to published spherical equivalent GWAS analyses suggest a greater influence of rare genetic variants, non-additive genetic effects, or environmental factors in the development of astigmatism.

Publication types

  • Meta-Analysis
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acid Phosphatase / genetics*
  • Asian Continental Ancestry Group
  • Astigmatism / diagnosis
  • Astigmatism / ethnology
  • Astigmatism / genetics*
  • Astigmatism / pathology
  • Claudins / genetics*
  • Cohort Studies
  • Cornea / metabolism
  • Cornea / pathology
  • Corneal Diseases / diagnosis
  • Corneal Diseases / ethnology
  • Corneal Diseases / genetics*
  • Corneal Diseases / pathology
  • European Continental Ancestry Group
  • Gene Expression
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics*
  • Odds Ratio
  • Polymorphism, Single Nucleotide
  • Receptor, Platelet-Derived Growth Factor alpha / genetics*
  • Software


  • CLDN7 protein, human
  • Claudins
  • Intracellular Signaling Peptides and Proteins
  • TNFAIP8L3 protein, human
  • Receptor, Platelet-Derived Growth Factor alpha
  • ACP2 protein, human
  • Acid Phosphatase