WNT10A exonic variant increases the risk of keratoconus by decreasing corneal thickness

Gabriel Cuellar-Partida, Hanriët Springelkamp, Sionne Lucas, Seyhan Yazar, Alex Hewitt, Adriana Iglesias, Grant Montgomery, Nicholas Martin, Craig Pennell, Elisabeth Van Leeuwen, Virginie Verhoeven, Albert Hofman, André Uitterlinden, Wishal Ramdas, Roger Wolfs, Johannes Vingerling, Matthew Brown, Richard Mills, Jamie Craig, Caroline KlaverCornelia van Duijn, Kathryn Burdon, Stuart Macgregor, David Mackey

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41 Citations (Scopus)


Keratoconus is a degenerative eye condition which results from thinning of the cornea and causes vision distortion. Treatments such as ultraviolet (UV) cross-linking have proved effective for management of keratoconus when performed in early stages of the disease. The central corneal thickness (CCT) is a highly heritable endophenotype of keratoconus, and it is estimated that up to 95% of its phenotypic variance is due to genetics. Genome-wide association efforts of CCT have identified common variants (i.e. minor allele frequency (MAF) >5%). However, these studies typically ignore the large set of exonic variants whose MAF is usually low. In this study, we performed a CCT exome-wide association analysis in a sample of 1029 individuals froma population-based study in Western Australia. We identified a genome-wide significant exonic variant rs121908120 (P = 6.63 × 10-10) in WNT10A. This gene is 437 kb from a gene previously associated with CCT (USP37). We showed in a conditional analysis that the WNT10A variant completely accounts for the signal previously seen at USP37. We replicated our finding in independent samples from the Brisbane Adolescent Twin Study, Twin Eye Study in Tasmania and the Rotterdam Study. Further, we genotyped rs121908120 in 621 keratoconus cases and compared the frequency to a sample of 1680 unscreened controls from the Queensland Twin Registry. We found that rs121908120 increases the risk of keratoconus two times (odds ratio 2.03, P = 5.41×10-5).

Original languageEnglish
Pages (from-to)5060-5068
Number of pages9
JournalHuman Molecular Genetics
Issue number17
Publication statusPublished - 2015


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