A multi-ethnic genome-wide association study implicates collagen matrix integrity and cell differentiation pathways in keratoconus

Alison J. Hardcastle, Petra Liskova, Yelena Bykhovskaya, Bennet J. McComish, Alice E. Davidson, Chris F. Inglehearn, Xiaohui Li, Hélène Choquet, Mahmoud Habeeb, Sionne E.M. Lucas, Srujana Sahebjada, Nikolas Pontikos, Karla E.Rojas Lopez, Anthony P. Khawaja, Manir Ali, Lubica Dudakova, Pavlina Skalicka, Bart T.H. Van Dooren, Annette J.M. Geerards, Christoph W. HaudumValeria Lo Faro, Abi Tenen, Mark J. Simcoe, Karina Patasova, Darioush Yarrand, Jie Yin, Salina Siddiqui, Aine Rice, Layal Abi Farraj, Yii Der Ida Chen, Jugnoo S. Rahi, Ronald M. Krauss, Elisabeth Theusch, Jac C. Charlesworth, Loretta Szczotka-Flynn, Carmel Toomes, Magda A. Meester-Smoor, Andrea J. Richardson, Paul A. Mitchell, Kent D. Taylor, Ronald B. Melles, Anthony J. Aldave, Richard A. Mills, Ke Cao, Elsie Chan, Mark D. Daniell, Jie Jin Wang, Jerome I. Rotter, Alex W. Hewitt, Stuart MacGregor, Caroline C.W. Klaver, Wishal D. Ramdas, Jamie E. Craig, Sudha K. Iyengar, David O’Brart, Eric Jorgenson, Paul N. Baird, Yaron S. Rabinowitz, Kathryn P. Burdon, Chris J. Hammond, Stephen J. Tuft, Pirro G. Hysi

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    Keratoconus is characterised by reduced rigidity of the cornea with distortion and focal thinning that causes blurred vision, however, the pathogenetic mechanisms are unknown. It can lead to severe visual morbidity in children and young adults and is a common indication for corneal transplantation worldwide. Here we report the first large scale genome-wide association study of keratoconus including 4,669 cases and 116,547 controls. We have identified significant association with 36 genomic loci that, for the first time, implicate both dysregulation of corneal collagen matrix integrity and cell differentiation pathways as primary disease-causing mechanisms. The results also suggest pleiotropy, with some disease mechanisms shared with other corneal diseases, such as Fuchs endothelial corneal dystrophy. The common variants associated with keratoconus explain 12.5% of the genetic variance, which shows potential for the future development of a diagnostic test to detect susceptibility to disease.

    Original languageEnglish
    Article number266
    Number of pages13
    JournalCommunications Biology
    Publication statusPublished - 1 Mar 2021


    • Keratoconus
    • collagen matrix integrity
    • rigidity of the cornea
    • severe visual morbidity
    • corneal transplantation
    • Fuchs endothelial corneal dystrophy


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