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

Rupal L. Shah, Qing Li, Wanting Zhao, Milly S. Tedja, J. Willem L. Tideman, Anthony P. Khawaja, Qiao Fan, Seyhan Yazar, Katie M. Williams, Virginie J.M. Verhoeven, Jing Xie, Ya Xing Wang, Moritz Hess, Stefan Nickels, Karl J. Lackner, Olavi Pärssinen, Juho Wedenoja, Ginevra Biino, Maria Pina Concas, André UitterlindenFernando Rivadeneira, Vincent W.V. Jaddoe, Pirro G. Hysi, Xueling Sim, Nicholas Tan, Yih Chung Tham, Sonoko Sensaki, Albert Hofman, Johannes R. Vingerling, Jost B. Jonas, Paul Mitchell, Christopher J. Hammond, René Höhn, Paul N. Baird, Tien Yin Wong, Chinfsg Yu Cheng, Yik Ying Teo, David A. Mackey, Cathy Williams, Seang Mei Saw, Caroline C.W. Klaver, Jeremy A. Guggenheim, Joan E. Bailey-Wilson, The CREAM Consortium

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5 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)127-142
Number of pages16
JournalMolecular Vision
Publication statusPublished - 5 Feb 2018
Externally publishedYes

Cite this

Shah, R. L., Li, Q., Zhao, W., Tedja, M. S., Tideman, J. W. L., Khawaja, A. P., Fan, Q., Yazar, S., Williams, K. M., Verhoeven, V. J. M., Xie, J., Wang, Y. X., Hess, M., Nickels, S., Lackner, K. J., Pärssinen, O., Wedenoja, J., Biino, G., Concas, M. P., ... The CREAM Consortium (2018). A genome-wide association study of corneal astigmatism: The CREAM consortium. Molecular Vision, 24, 127-142. http://www.molvis.org/molvis/v24/127/mv-v24-127.pdf