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Resequencing of candidate genes for Keratoconus reveals a role for Ehlers–Danlos Syndrome genes

European Journal of Human Genetics volume 29, pages 1745–1755 (2021)Cite this article

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Abstract

The involvement of genetic factors in the pathogenesis of KC has long been recognized but the identification of variants affecting the underlying protein functions has been challenging. In this study, we selected 34 candidate genes for KC based on previous whole-exome sequencing (WES) and the literature, and resequenced them in 745 KC patients and 810 ethnically matched controls from Belgium, France and Italy. Data analysis was performed using the single variant association test as well as gene-based mutation burden and variance components tests. In our study, we detected enrichment of genetic variation across multiple gene-based tests for the genes COL2A1, COL5A1, TNXB, and ZNF469. The top hit in the single variant association test was obtained for a common variant in the COL12A1 gene. These associations were consistently found across independent subpopulations. Interestingly, COL5A1, TNXB, ZNF469 and COL12A1 are all known Ehlers–Danlos Syndrome (EDS) genes. Though the co-occurrence of KC and EDS has been reported previously, this study is the first to demonstrate a consistent role of genetic variants in EDS genes in the etiology of KC. In conclusion, our data show a shared genetic etiology between KC and EDS, and clearly confirm the currently disputed role of ZNF469 in disease susceptibility for KC.

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Fig. 1: Evaluation of significance for single variant association tests.
Fig. 2: Evaluation of significance in gene-based tests.
Fig. 3: Overrepresentation of known Ehlers-Danlos Syndrome genes.

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Data availability

The datasets generated and/or analyzed during the current study have been submitted to the European Genome-Phenome Archive, accession number EGAD00001006825.

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Funding

This study was supported by funding from the BELSPO-IAP program (project IAP P7/43-BeMGI to GVC), the FRO and Braille Liga. HV was supported by a PhD grant from the IWT (grant no. 131526). GVC was supported by the FWO (grant no. 12D1717N). VS was supported by a Bourse Rétina France 2013 and Bourse Rétina France 2017. The supporting organizations had no role in the design or conduct of this research.

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Author notes

  1. These authors contributed equally: Erik Fransen, Hanne Valgaeren

Authors and Affiliations

  1. Center of Medical Genetics, University of Antwerp & Antwerp University Hospital, Prins Boudewijnlaan 43, 2650, Edegem, Antwerp, Belgium

    Erik Fransen, Hanne Valgaeren, Katleen Janssens, Manou Sommen, Raphael De Ridder, Geert Vandeweyer, Geert Mortier & Guy Van Camp

  2. StatUa Center for Statistics, University of Antwerp, Antwerp, Belgium

    Erik Fransen

  3. Department of Ophthalmology, Antwerp University Hospital, Wilrijkstraat 10, 2650, Edegem, Antwerp, Belgium

    Katleen Janssens & Carina Koppen

  4. IRCCS Casa Sollievo della Sofferenza, UOC Genetica Medica, San Giovanni Rotondo, Italy

    Luigi Bisceglia

  5. Department of Ophthalmology, Pierre-Paul Riquet Hospital, Toulouse University Hospital, Toulouse, France

    Vincent Soler & François Malecaze

  6. Department of Human Genetics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Geert Grooteplein 10, 6525 GA, Nijmegen, the Netherlands

    Alexander Hoischen

  7. Department of Internal Medicine and Radboud Center for Infectious Diseases (RCI), Radboud University Medical Center, 6500 HB, Nijmegen, the Netherlands

    Alexander Hoischen

  8. Department Ophthalmology, Visual optics and Visual rehabilitation, University of Antwerp, Universiteitsplein 1, B-2610, Antwerp, Belgium

    Carina Koppen

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Correspondence to Guy Van Camp.

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Fransen, E., Valgaeren, H., Janssens, K. et al. Resequencing of candidate genes for Keratoconus reveals a role for Ehlers–Danlos Syndrome genes. Eur J Hum Genet 29, 1745–1755 (2021). https://doi.org/10.1038/s41431-021-00849-2

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