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

  • Author(s): Iglesias, Adriana I
  • Mishra, Aniket
  • Vitart, Veronique
  • Bykhovskaya, Yelena
  • Höhn, René
  • Springelkamp, Henriët
  • Cuellar-Partida, Gabriel
  • Gharahkhani, Puya
  • Bailey, Jessica N Cooke
  • Willoughby, Colin E
  • Li, Xiaohui
  • Yazar, Seyhan
  • Nag, Abhishek
  • Khawaja, Anthony P
  • Polašek, Ozren
  • Siscovick, David
  • Mitchell, Paul
  • Tham, Yih Chung
  • Haines, Jonathan L
  • Kearns, Lisa S
  • Hayward, Caroline
  • Shi, Yuan
  • van Leeuwen, Elisabeth M
  • Taylor, Kent D
  • Blue Mountains Eye Study—GWAS group
  • Bonnemaijer, Pieter
  • Rotter, Jerome I
  • Martin, Nicholas G
  • Zeller, Tanja
  • Mills, Richard A
  • Souzeau, Emmanuelle
  • Staffieri, Sandra E
  • Jonas, Jost B
  • Schmidtmann, Irene
  • Boutin, Thibaud
  • Kang, Jae H
  • Kang, Jae H
  • Lucas, Sionne EM
  • Wong, Tien Yin
  • Beutel, Manfred E
  • Wilson, James F
  • NEIGHBORHOOD Consortium
  • Wellcome Trust Case Control Consortium 2 (WTCCC2)
  • Uitterlinden, André G
  • Vithana, Eranga N
  • Foster, Paul J
  • Hysi, Pirro G
  • Hewitt, Alex W
  • Khor, Chiea Chuen
  • Pasquale, Louis R
  • Montgomery, Grant W
  • Klaver, Caroline CW
  • Aung, Tin
  • Pfeiffer, Norbert
  • Mackey, David A
  • Hammond, Christopher J
  • Cheng, Ching-Yu
  • Craig, Jamie E
  • Rabinowitz, Yaron S
  • Wiggs, Janey L
  • Burdon, Kathryn P
  • van Duijn, Cornelia M
  • MacGregor, Stuart
  • et al.

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.

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