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

Adriana I. Iglesias, Aniket Mishra, Véronique Vitart, Yelena Bykhovskaya, René Höhn, Henriette 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 S. Siscovick, Paul G. Mitchell, Yih Chung Tham, Jonathan L. Haines, Lisa S. KearnsCaroline Hayward, Yuan Shi, Elisabeth M. Van Leeuwen, Kent D. Taylor, Jiejin Wang, Elena Rochtchina, John R. Attia, Rodney J. Scott, Elizabeth G. Holliday, Tien Yin Wong, Paul N. Baird, Jing Xie, Michael Inouye, Ananth C. Viswanathan, Xueling Sim, Pieter W.M. Bonnemaijer, Jerome I. Rotter, Nicholas G. Martin, Tanja Zeller, Richard A.D. Mills, Emmanuelle Souzeau, Sandra Elfride Staffieri, Jost Bruno Jonas, Irene Schmidtmann, Thibaud S. Boutin, Jaehee Kang, Sionne E.M. Lucas, Manfred E. Beutel, James F. Wilson, Peter J. Donnelly, Inês Barroso, Jenefer Mary Blackwell, Elvira Bramon, Matthew A. Brown, Juan Pablo Casas, Aiden Corvin, Panos Deloukas, Audrey Duncanson, Janusz Jankowski, Hugh Stephen Markus, Christopher G. Mathew, Colin Neil Palmer, Robert J. 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 D. Pearson, Amy Strange, Zhan Su, Damjan Vukcevic, Cordelia F. Langford, Sarah E. Hunt, Sarah J. Edkins, Rhian G. Gwilliam, Hannah Blackburn, Suzannah J. Bumpstead, Serge Dronov, Matthew W. Gillman, Emma Gray, Naomi Hammond, Alagurevathi Jayakumar, Owen T. McCann, Jennifer Liddle, Simon C. Potter, Rathi Sri Ravindrarajah, Michelle Ricketts, Matthew J. Waller, Paul Weston, Sara Widaa, Pamela Whittaker, Robert Rand Allingham, Murray H. Brilliant, Donald L. Budenz, William Gerard Christen, John H. Fingert, David Steven Friedman, Douglas E. Gaasterland, Terry M. Gaasterland, Michael A. Hauser, Peter Kraft, Richard K. Lee, Paul R. Lichter, Yutao Liu, Stephanie J. Loomis, Sayoko E. Moroi, Brian W. Kunkle, Anthony T. Realini, Julia E. Richards, Joel S. Schuman, William K. Scott, Kuldev Singh, Arthur J. Sit, Arthur J. Sit, Robert N. Weinreb, Gadi Wollstein, Donald J. Zack, Donald J. Zack, André G. Uitterlinden, Eranga Nishanthie Vithana, Paul J. Foster, Pirro G. Hysi, A. 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 Evan Craig, Yaron S. Rabinowitz, Janey L. Wiggs, Kathryn P. Burdon, Cornelia M. Van Duijn, Stuart MacGregor

Research output: Contribution to journalArticle

16 Citations (Scopus)

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)1864-1864
Number of pages1
JournalNature Communications
Volume10
Issue number1
DOIs
Publication statusPublished - 2019

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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. S., Mitchell, P. G., Tham, Y. C., Haines, J. L., ... MacGregor, S. (2019). Cross-ancestry genome-wide association analysis of corneal thickness strengthens link between complex and Mendelian eye diseases. Nature Communications, 10(1), 1864-1864. [1864]. https://doi.org/10.1038/s41467-018-03646-6