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

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

Author information

1
School of Optometry & Vision Sciences, Cardiff University, Cardiff, UK.
2
Computational and Statistical Genomics Branch, National Human Genome Research Institute, National Institutes of Health, Baltimore, MD, USA.
3
Singapore Eye Research Institute, Singapore National Eye Centre, Singapore, Singapore.
4
Centre for Quantitative Medicine, Duke-NUS Medical School, Singapore, Singapore.
5
Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.
6
Department of Ophthalmology, Erasmus Medical Center, Rotterdam, The Netherlands.
7
Department of Public Health and Primary Care, Institute of Public Health, University of Cambridge School of Clinical Medicine, Cambridge, UK.
8
NIHR Biomedical Research Centre, Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, London, UK.
9
Institute of Genetics and Molecular Medicine, Medical Research Council Human Genetics Unit, University of Edinburgh, Edinburgh, UK.
10
Centre for Ophthalmology and Visual Science, Lions Eye Institute, University of Western Australia, Perth, Australia.
11
Department of Ophthalmology, King's College London, London, UK.
12
Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, Melbourne, Victoria, Australia.
13
Ophthalmology, Department of Surgery, University of Melbourne, Melbourne, Australia.
14
Beijing Institute of Ophthalmology, Beijing Key Laboratory of Ophthalmology and Visual Sciences, Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University; Beijing, China.
15
Institute for Medical Biostatistics, Epidemiology and Informatics, University Medical Center Mainz, Mainz, Germany.
16
Department of Ophthalmology, University Medical Center Mainz, Mainz, Germany.
17
Institute for Clinical Chemistry and Laboratory Medicine, University Medical Center Mainz, Mainz, Germany.
18
Department of Ophthalmology, Central Hospital of Central Finland, Jyväskylä, Finland.
19
Gerontology Research Center, Faculty of Sport and Health Sciences, University of Jyväskylä, Finland.
20
Department of Health Sciences, University of Jyväskylä, Jyväskylä, Finland.
21
Department of Ophthalmology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
22
Department of Public Health, University of Helsinki, Helsinki, Finland.
23
Institute of Molecular Genetics, National Research Council of Italy, Pavia, Italy.
24
Institute for Maternal and Child Health - IRCCS 'Burlo Garofolo', Trieste, Italy.
25
Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.
26
Department of Pediatrics Erasmus Medical Center, Rotterdam, the Netherlands.
27
Saw Swee Hock School of Public Health, National University of Singapore, Singapore, Singapore.
28
Department of Ophthalmology, National University Hospital, Singapore.
29
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA.
30
Department of Ophthalmology, Medical Faculty Mannheim of the University Heidelberg, Mannheim, Germany.
31
Department of Ophthalmology, Western Sydney Local Health District, Sydney, Australia.
32
Centre for Vision Research, Westmead Institute for Medical Research, University of Sydney, Sydney, Australia.
33
Department of Ophthalmology, Inselspital, University Hospital Bern, University of Bern, Bern, Switzerland.
34
Ophthalmology & Visual Sciences Academic Clinical Program (Eye ACP), Duke-NUS Medical School, Singapore.
35
Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
36
Department of Statistics and Applied Probability, National University of Singapore, Singapore.
37
Division of Human Genetics, Genome Institute of Singapore, Singapore.
38
School of Social and Community Medicine, University of Bristol, Bristol, UK.
39
Department of Ophthalmology, Radboud University Medical Center, Nijmegen, the Netherlands.

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.

PMID:
29422769
PMCID:
PMC5800430
[Indexed for MEDLINE]
Free PMC Article

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