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Common Genetic Variants near the Brittle Cornea Syndrome Locus ZNF469 Influence the Blinding Disease Risk Factor Central Corneal Thickness

Author

Listed:
  • Yi Lu
  • David P Dimasi
  • Pirro G Hysi
  • Alex W Hewitt
  • Kathryn P Burdon
  • Tze'Yo Toh
  • Jonathan B Ruddle
  • Yi Ju Li
  • Paul Mitchell
  • Paul R Healey
  • Grant W Montgomery
  • Narelle Hansell
  • Timothy D Spector
  • Nicholas G Martin
  • Terri L Young
  • Christopher J Hammond
  • Stuart Macgregor
  • Jamie E Craig
  • David A Mackey

Abstract

Central corneal thickness (CCT), one of the most highly heritable human traits (h2 typically>0.9), is important for the diagnosis of glaucoma and a potential risk factor for glaucoma susceptibility. We conducted genome-wide association studies in five cohorts from Australia and the United Kingdom (total N = 5058). Three cohorts were based on individually genotyped twin collections, with the remaining two cohorts genotyped on pooled samples from singletons with extreme trait values. The pooled sample findings were validated by individual genotyping the pooled samples together with additional samples also within extreme quantiles. We describe methods for efficient combined analysis of the results from these different study designs. We have identified and replicated quantitative trait loci on chromosomes 13 and 16 for association with CCT. The locus on chromosome 13 (nearest gene FOXO1) had an overall meta-analysis p-value for all the individually genotyped samples of 4.6×10−10. The locus on chromosome 16 was associated with CCT with p = 8.95×10−11. The nearest gene to the associated chromosome 16 SNPs was ZNF469, a locus recently implicated in Brittle Cornea Syndrome (BCS), a very rare disorder characterized by abnormal thin corneas. Our findings suggest that in addition to rare variants in ZNF469 underlying CCT variation in BCS patients, more common variants near this gene may contribute to CCT variation in the general population.Author Summary: Central corneal thickness (CCT) is an important eye measurement. It has been considered as a prognosticator for the development of glaucoma, with a thin cornea potentially increasing the risk of developing a subtype known as open-angle glaucoma. CCT is highly heritable, yet its genetic determinants are poorly characterized. We have revealed two loci near gene FOXO1 and ZNF469 associated with CCT in this multi-stage genome-wide association study examining over 5,000 samples. It is of particular interest that, while rare mutations in ZNF469 cause Brittle Cornea Syndrome, more common variants near this gene also contribute to CCT variation in the general population. Furthermore, given the relation between CCT and glaucoma, results from our CCT studies will implement the search for the disease-susceptibility genes of glaucoma.

Suggested Citation

  • Yi Lu & David P Dimasi & Pirro G Hysi & Alex W Hewitt & Kathryn P Burdon & Tze'Yo Toh & Jonathan B Ruddle & Yi Ju Li & Paul Mitchell & Paul R Healey & Grant W Montgomery & Narelle Hansell & Timothy D , 2010. "Common Genetic Variants near the Brittle Cornea Syndrome Locus ZNF469 Influence the Blinding Disease Risk Factor Central Corneal Thickness," PLOS Genetics, Public Library of Science, vol. 6(5), pages 1-10, May.
  • Handle: RePEc:plo:pgen00:1000947
    DOI: 10.1371/journal.pgen.1000947
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    Cited by:

    1. David P Dimasi & Alex W Hewitt & Kenneth Kagame & Sam Ruvama & Ludovica Tindyebwa & Bastien Llamas & Kirsty A Kirk & Paul Mitchell & Kathryn P Burdon & Jamie E Craig, 2011. "Ethnic and Mouse Strain Differences in Central Corneal Thickness and Association with Pigmentation Phenotype," PLOS ONE, Public Library of Science, vol. 6(8), pages 1-10, August.
    2. Leonieke M E van Koolwijk & Wishal D Ramdas & M Kamran Ikram & Nomdo M Jansonius & Francesca Pasutto & Pirro G Hysi & Stuart Macgregor & Sarah F Janssen & Alex W Hewitt & Ananth C Viswanathan & Jacoli, 2012. "Common Genetic Determinants of Intraocular Pressure and Primary Open-Angle Glaucoma," PLOS Genetics, Public Library of Science, vol. 8(5), pages 1-14, May.
    3. Andrew R. Hamel & Wenjun Yan & John M. Rouhana & Aboozar Monovarfeshani & Xinyi Jiang & Puja A. Mehta & Jayshree Advani & Yuyang Luo & Qingnan Liang & Skanda Rajasundaram & Arushi Shrivastava & Kather, 2024. "Integrating genetic regulation and single-cell expression with GWAS prioritizes causal genes and cell types for glaucoma," Nature Communications, Nature, vol. 15(1), pages 1-25, December.

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