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

Adriana I. Iglesias, Veronique Vitart, 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. van Leeuwen, Kent D. Taylor, Blue Mountains Eye Study—GWAS group, Pieter Bonnemaijer, Jerome I. Rotter, Nicholas G. MartinTanja 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, NEIGHBORHOOD Consortium, Wellcome Trust Case Control Consortium 2 (WTCCC2), 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, Norbet 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

Research output: Contribution to journalArticlepeer-review


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
JournalNature Communications
Publication statusPublished - 14 May 2018


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