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. Kearns, Caroline Hayward, Yuan Shi, Elisabeth M. Leeuwen, Kent D. Taylor, Pieter Bonnemaijer, Jerome I. Rotter, Nicholas G. Martin, Tanja Zeller, Richard A. Mills, Emmanuelle Souzeau, 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, 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. Duijn and Stuart MacGregor ()
Additional contact information
Adriana I. Iglesias: Erasmus Medical Center
Aniket Mishra: Bordeaux Population Health Research Center
Veronique Vitart: University of Edinburgh
Yelena Bykhovskaya: Cedars-Sinai Medical Center
René Höhn: University Medical Center Mainz
Henriët Springelkamp: Erasmus Medical Center
Gabriel Cuellar-Partida: QIMR Berghofer Medical Research Institute
Puya Gharahkhani: QIMR Berghofer Medical Research Institute
Jessica N. Cooke Bailey: Case Western Reserve University
Colin E. Willoughby: Ulster University
Xiaohui Li: Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center
Seyhan Yazar: University of Edinburgh
Abhishek Nag: King’s College London
Anthony P. Khawaja: University of Cambridge School of Clinical Medicine
Ozren Polašek: University of Split
David Siscovick: University of Washington
Paul Mitchell: University of Sydney
Yih Chung Tham: Singapore National Eye Centre
Jonathan L. Haines: Case Western Reserve University
Lisa S. Kearns: Royal Victorian Eye and Ear Hospital
Caroline Hayward: University of Edinburgh
Yuan Shi: Singapore National Eye Centre
Elisabeth M. Leeuwen: Erasmus Medical Center
Kent D. Taylor: Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center
Pieter Bonnemaijer: Erasmus Medical Center
Jerome I. Rotter: Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center
Nicholas G. Martin: QIMR Berghofer Medical Research Institute
Tanja Zeller: University Heart Center Hamburg
Richard A. Mills: Flinders University
Emmanuelle Souzeau: Flinders University
Sandra E. Staffieri: Royal Victorian Eye and Ear Hospital
Jost B. Jonas: Medical Faculty Mannheim of the Ruprecht-Karls-University of Heidelberg
Irene Schmidtmann: University Medical Center Mainz
Thibaud Boutin: University of Edinburgh
Jae H. Kang: Brigham and Women’s Hospital
Sionne E. M. Lucas: University of Tasmania
Tien Yin Wong: Singapore National Eye Centre
Manfred E. Beutel: University Medical Center Mainz
James F. Wilson: University of Edinburgh
André G. Uitterlinden: Erasmus Medical Center
Eranga N. Vithana: Singapore National Eye Centre
Paul J. Foster: Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology
Pirro G. Hysi: King’s College London
Alex W. Hewitt: Royal Victorian Eye and Ear Hospital
Chiea Chuen Khor: Genome Institute of Singapore
Louis R. Pasquale: Brigham and Women’s Hospital
Grant W. Montgomery: QIMR Berghofer Medical Research Institute
Caroline C. W. Klaver: Erasmus Medical Center
Tin Aung: Singapore National Eye Centre
Norbert Pfeiffer: University Medical Center Mainz
David A. Mackey: University of Western Australia, Lions Eye Institute
Christopher J. Hammond: King’s College London
Ching-Yu Cheng: Singapore National Eye Centre
Jamie E. Craig: Flinders University
Yaron S. Rabinowitz: Cedars-Sinai Medical Center
Janey L. Wiggs: Harvard Medical School and Massachusetts Eye and Ear Infirmary
Kathryn P. Burdon: University of Tasmania
Cornelia M. Duijn: Erasmus Medical Center
Stuart MacGregor: QIMR Berghofer Medical Research Institute

Nature Communications, 2018, vol. 9, issue 1, 1-11

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-03646-6

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