TY - JOUR T1 - A genome-wide association study of corneal astigmatism: The CREAM Consortium. JF - Mol Vis Y1 - 2018 A1 - Shah, Rupal L A1 - Li, Qing A1 - Zhao, Wanting A1 - Tedja, Milly S A1 - Tideman, J Willem L A1 - Khawaja, Anthony P A1 - Fan, Qiao A1 - Yazar, Seyhan A1 - Williams, Katie M A1 - Verhoeven, Virginie J M A1 - Xie, Jing A1 - Wang, Ya Xing A1 - Hess, Moritz A1 - Nickels, Stefan A1 - Lackner, Karl J A1 - Pärssinen, Olavi A1 - Wedenoja, Juho A1 - Biino, Ginevra A1 - Concas, Maria Pina A1 - Uitterlinden, André A1 - Rivadeneira, Fernando A1 - Jaddoe, Vincent W V A1 - Hysi, Pirro G A1 - Sim, Xueling A1 - Tan, Nicholas A1 - Tham, Yih-Chung A1 - Sensaki, Sonoko A1 - Hofman, Albert A1 - Vingerling, Johannes R A1 - Jonas, Jost B A1 - Mitchell, Paul A1 - Hammond, Christopher J A1 - Höhn, René A1 - Baird, Paul N A1 - Wong, Tien-Yin A1 - Cheng, Chinfsg-Yu A1 - Teo, Yik Ying A1 - Mackey, David A A1 - Williams, Cathy A1 - Saw, Seang-Mei A1 - Klaver, Caroline C W A1 - Guggenheim, Jeremy A A1 - Bailey-Wilson, Joan E KW - Acid Phosphatase KW - Asian Continental Ancestry Group KW - Astigmatism KW - Claudins KW - Cohort Studies KW - Cornea KW - Corneal Diseases KW - European Continental Ancestry Group KW - Gene Expression KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Humans KW - Intracellular Signaling Peptides and Proteins KW - Odds Ratio KW - Polymorphism, Single Nucleotide KW - Receptor, Platelet-Derived Growth Factor alpha KW - Software AB -

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=5.55×10. 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.

VL - 24 U1 - http://www.ncbi.nlm.nih.gov/pubmed/29422769?dopt=Abstract ER -