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Meta-Analysis
, 24, 127-142
eCollection

A Genome-Wide Association Study of Corneal Astigmatism: The CREAM Consortium

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Meta-Analysis

A Genome-Wide Association Study of Corneal Astigmatism: The CREAM Consortium

Rupal L Shah et al. Mol Vis.

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 (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.

Figures

Figure 1
Figure 1
Manhattan plot showing most strongly associated markers in the GWAS fixed-effects meta-analysis for European and Asian participants of all ages combined (n=31,375). Red line: p=5×10−8, blue line: p=1×10−5.
Figure 2
Figure 2
Q-Q plot for the GWAS fixed-effects meta-analysis for European and Asian participants of all ages combined (n=31,375).
Figure 3
Figure 3
Region plot for the most strongly associated region in the GWAS fixed-effects meta-analysis for European and Asian participants of all ages combined (n=31,375).
Figure 4
Figure 4
Forest plot and summary table for lead variant rs7673984 across all cohorts. Studies listed above the dotted line are new cohorts not included in the only prior GWAS for corneal astigmatism [16]. EAF=effect allele frequency. (Note that rs7673984 was excluded from the Rotterdam-I cohort analysis during quality control filtering).

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