Cross-ancestry genome-wide association analysis of corneal thickness strengthens link between complex and Mendelian eye diseases

Adriana I. Iglesias, Aniket Mishra, Veronique Vitart, Yelena Bykhovskaya, René Höhn, Henriët Springelkamp, Gabriel Cuellar-Partida, Puya Gharahkhani, Jessica N.Cooke Bailey, Colin E. Willoughby, Xiaohui Li, Seyhan Yazar, Abhishek Nag, Anthony P. Khawaja, Ozren Polašek, David Siscovick, Paul Mitchell, Yih Chung Tham, Jonathan L. Haines, Lisa S. KearnsCaroline Hayward, Yuan Shi, Elisabeth M. Van Leeuwen, Kent D. Taylor, Jie Jin Wang, Elena Rochtchina, John Attia, Rodney Scott, Elizabeth G. Holliday, Paul N. Baird, Jing Xie, Michael Inouye, Ananth Viswanathan, Xueling Sim, Pieter Bonnemaijer, Jerome I. Rotter, Nicholas G. Martin, Tanja Zeller, Richard A. Mills, Sandra E. Staffieri, Jost B. Jonas, Irene Schmidtmann, Thibaud Boutin, Jae H. Kang, Sionne E.M. Lucas, Tien Yin Wong, Manfred E. Beutel, James F. Wilson, R. Rand Allingham, Murray H. Brilliant, Donald L. Budenz, William G. Christen, John Fingert, David S. Friedman, Douglas Gaasterland, Terry Gaasterland, Michael A. Hauser, Peter Kraft, Richard K. Lee, Paul R. Lichter, Yutao Liu, Stephanie J. Loomis, Sayoko E. Moroi, Margaret A. Pericak-Vance, Anthony Realini, Julia E. Richards, Joel S. Schuman, William K. Scott, Kuldev Singh, Arthur J. Sit, Douglas Vollrath, Robert N. Weinreb, Gadi Wollstein, Donald J. Zack, Kang Zhang, Peter Donnelly, Ines Barroso, Jenefer M. Blackwell, Elvira Bramon, Matthew A. Brown, Juan P. Casas, Aiden Corvin, Panos Deloukas, Audrey Duncanson, Janusz Jankowski, Hugh S. Markus, Christopher G. Mathew, Colin N.A. Palmer, Robert Plomin, Anna Rautanen, Stephen J. Sawcer, Richard C. Trembath, Nicholas W. Wood, Chris C.A. Spencer, Gavin Band, Céline Bellenguez, Colin Freeman, Garrett Hellenthal, Eleni Giannoulatou, Matti Pirinen, Richard Pearson, Amy Strange, Zhan Su, Damjan Vukcevic, Cordelia Langford, Sarah E. Hunt, Sarah Edkins, Rhian Gwilliam, Hannah Blackburn, Suzannah J. Bumpstead, Serge Dronov, Matthew Gillman, Emma Gray, Naomi Hammond, Alagurevathi Jayakumar, Owen T. McCann, Jennifer Liddle, Simon C. Potter, Radhi Ravindrarajah, Michelle Ricketts, Matthew Waller, Paul Weston, Sara Widaa, Pamela Whittaker, André G. Uitterlinden, Eranga N. Vithana, Paul J. Foster, Pirro G. Hysi, Alex W. Hewitt, Chiea Chuen Khor, Louis R. Pasquale, Grant W. Montgomery, Caroline C.W. Klaver, Tin Aung, Norbert Pfeiffer, David A. MacKey, Christopher J. Hammond, Ching Yu Cheng, Jamie E. Craig, Yaron S. Rabinowitz, Janey L. Wiggs, Kathryn P. Burdon, Cornelia M. Van Duijn, Stuart MacGregor

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    Abstract

    Central corneal thickness (CCT) is a highly heritable trait associated with complex eye diseases such as keratoconus and glaucoma. We perform a genome-wide association meta-analysis of CCT and identify 19 novel regions. In addition to adding support for known connective tissue-related pathways, pathway analyses uncover previously unreported gene sets. Remarkably, >20% of the CCT-loci are near or within Mendelian disorder genes. These included FBN1, ADAMTS2 and TGFB2 which associate with connective tissue disorders (Marfan, Ehlers-Danlos and Loeys-Dietz syndromes), and the LUM-DCN-KERA gene complex involved in myopia, corneal dystrophies and cornea plana. Using index CCT-increasing variants, we find a significant inverse correlation in effect sizes between CCT and keratoconus (r =-0.62, P = 5.30 × 10-5) but not between CCT and primary open-angle glaucoma (r =-0.17, P = 0.2). Our findings provide evidence for shared genetic influences between CCT and keratoconus, and implicate candidate genes acting in collagen and extracellular matrix regulation.

    Original languageEnglish
    Article number1864
    Pages (from-to)1-11
    Number of pages11
    JournalNature Communications
    Volume9
    Issue number1
    DOIs
    Publication statusPublished - 14 May 2018

    Keywords

    • corneal
    • corneal thickness
    • GWAS
    • meta-analysis

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    Iglesias, A. I., Mishra, A., Vitart, V., Bykhovskaya, Y., Höhn, R., Springelkamp, H., Cuellar-Partida, G., Gharahkhani, P., Bailey, J. N. C., Willoughby, C. E., Li, X., Yazar, S., Nag, A., Khawaja, A. P., Polašek, O., Siscovick, D., Mitchell, P., Tham, Y. C., Haines, J. L., ... MacGregor, S. (2018). Cross-ancestry genome-wide association analysis of corneal thickness strengthens link between complex and Mendelian eye diseases. Nature Communications, 9(1), 1-11. [1864]. https://doi.org/10.1038/s41467-018-03646-6