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

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Iglesias, A. I. | Mishra, Aniket | Vitart, V. | Bykhovskaya, Y. | Hohn, R. | Springelkamp, H. | Cuellar-Partida, G. | Gharahkhani, P. | Bailey, J. N. C. | Willoughby, C. E. | Li, Xiaojian | Yazar, S. | Nag, A. | Khawaja, A. P. | Polasek, O. | Siscovick, D. | Mitchell, P. | Tham, Y. C. | Haines, J. L. | Kearns, L. S. | Hayward, C. | Shi, Y. | van Leeuwen, E. M. | Taylor, K. D. | Bonnemaijer, P. | Rotter, J. I. | Martin, N. G. | Zeller, T. | Mills, R. A. | Staffieri, S. E. | Jonas, J. B. | Schmidtmann, I. | Boutin, T. | Kang, J. H. | Lucas, S. E. M. | Wong, T. Y. | Beutel, M. E. | Wilson, J. F. | Uitterlinden, A. G. | Vithana, E. N. | Foster, P. J. | Hysi, P. G. | Hewitt, A. W. | Khor, C. C. | Pasquale, L. R. | Montgomery, G. W. | Klaver, C. C. W. | Aung, T. | Pfeiffer, N. | Mackey, D. A. | Hammond, C. J. | Cheng, C. Y. | Craig, J. E. | Rabinowitz, Y. S. | Wiggs, J. L. | Burdon, K. P. | van Duijn, C. M. | Macgregor, S.

Edité par CCSD ; Nature Publishing Group -

International audience. 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 x 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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