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 van 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 van Duijn
  • Stuart MacGregor
  • Blue Mountains Eye Study—GWAS group


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.

Bibliographical metadata

Original languageEnglish
Publication statusPublished - 14.05.2018
PubMed 29760442