@article {10426, title = {A genome-wide association study of corneal astigmatism: The CREAM Consortium.}, journal = {Mol Vis}, volume = {24}, year = {2018}, month = {2018}, pages = {127-142}, abstract = {

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 () gene: top SNP: rs7673984, odds ratio=1.12 (95\% CI:1.08-1.16), p=5.55{\texttimes}10. 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 (), acid phosphatase 2, lysosomal (), and TNF alpha-induced protein 8 like 3 ().

Conclusions: In addition to replicating a previously identified genome-wide significant locus for corneal astigmatism near the gene, gene-based analysis identified three novel candidate genes, , , and , 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.

}, keywords = {Acid Phosphatase, Asian Continental Ancestry Group, Astigmatism, Claudins, Cohort Studies, Cornea, Corneal Diseases, European Continental Ancestry Group, Gene Expression, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Intracellular Signaling Peptides and Proteins, Odds Ratio, Polymorphism, Single Nucleotide, Receptor, Platelet-Derived Growth Factor alpha, Software}, issn = {1090-0535}, author = {Shah, Rupal L and Li, Qing and Zhao, Wanting and Tedja, Milly S and Tideman, J Willem L and Khawaja, Anthony P and Fan, Qiao and Yazar, Seyhan and Williams, Katie M and Verhoeven, Virginie J M and Xie, Jing and Wang, Ya Xing and Hess, Moritz and Nickels, Stefan and Lackner, Karl J and P{\"a}rssinen, Olavi and Wedenoja, Juho and Biino, Ginevra and Concas, Maria Pina and Uitterlinden, Andr{\'e} and Rivadeneira, Fernando and Jaddoe, Vincent W V and Hysi, Pirro G and Sim, Xueling and Tan, Nicholas and Tham, Yih-Chung and Sensaki, Sonoko and Hofman, Albert and Vingerling, Johannes R and Jonas, Jost B and Mitchell, Paul and Hammond, Christopher J and H{\"o}hn, Ren{\'e} and Baird, Paul N and Wong, Tien-Yin and Cheng, Chinfsg-Yu and Teo, Yik Ying and Mackey, David A and Williams, Cathy and Saw, Seang-Mei and Klaver, Caroline C W and Guggenheim, Jeremy A and Bailey-Wilson, Joan E} }