A common variant mapping to CACNA1A is associated with susceptibility to exfoliation syndrome

T. Aung, M. Ozaki, T. Mizoguchi, R.R. Allingham, Z. Li, A. Haripriya, S. Nakano, S. Uebe, J.M. Harder, A.S.Y. Chan, M.C. Lee, K.P. Burdon, Y.S. Astakhov, K.K. Abu-Amero, J.C. Zenteno, Y. Nilgün, T. Zarnowski, M. Pakravan, L.A. Safieh, L. JiaY.X. Wang, S. Williams, D. Paoli, P.G. Schlottmann, L. Huang, K.S. Sim, J.N. Foo, M. Nakano, Y. Ikeda, R.S. Kumar, M. Ueno, S.-I. Manabe, K. Hayashi, S. Kazama, R. Ideta, Y. Mori, K. Miyata, K. Sugiyama, T. Higashide, E. Chihara, K. Inoue, S. Ishiko, A. Yoshida, M. Yanagi, Y. Kiuchi, M. Aihara, T. Ohashi, T. Sakurai, T. Sugimoto, H. Chuman, F. Matsuda, K. Yamashiro, N. Gotoh, M. Miyake, S.Y. Astakhov, E.A. Osman, S.A. Al-Obeidan, O. Owaidhah, L. Al-Jasim, S.A. Shahwan, R.A. Fogarty, P. Leo, Y. Yetkin, C. Ouz, M.R. Kanavi, A.N. Beni, S. Yazdani, E.L. Akopov, K.-Y. Toh, G.R. Howell, A.C. Orr, Y. Goh, W.Y. Meah, S.Q. Peh, E. Kosior-Jarecka, U. Lukasik, M. Krumbiegel, E.N. Vithana, T.Y. Wong, Y. Liu, A.E.A. Koch, P. Challa, R.M. Rautenbach, David Mackey, A.W. Hewitt, P. Mitchell, J.J. Wang, A. Ziskind, T. Carmichael, R. Ramakrishnan, K. Narendran, R. Venkatesh, S. Vijayan, P. Zhao, X. Chen, D. Guadarrama-Vallejo, C.Y. Cheng, S.A. Perera, R. Husain, S.-L. Ho, U.-C. Welge-Luessen, C. Mardin, U. Schloetzer-Schrehardt, A.M. Hillmer, S. Herms, S. Moebus, M.M. Nöthen, N. Weisschuh, R. Shetty, A. Ghosh, Y.Y. Teo, M.A. Brown, I. Lischinsky, J.G. Crowston, M. Coote, B. Zhao, J. Sang, N. Zhang, Q. You, V. Vysochinskaya, P. Founti, A. Chatzikyriakidou, A. Lambropoulos, E. Anastasopoulos, A.L. Coleman, M.R. Wilson, D.J. Rhee, J.H. Kang, I. May-Bolchakova, S. Heegaard, K. Mori, W.L.M. Alward, J.B. Jonas, L. Xu, J.M. Liebmann, B. Chowbay, E. Schaeffeler, M. Schwab, F. Lerner, N. Wang, Z. Yang, P. Frezzotti, S. Kinoshita, J.H. Fingert, M. Inatani, K. Tashiro, A. Reis, D.P. Edward, L.R. Pasquale, T. Kubota, J.L. Wiggs, F. Pasutto, F. Topouzis, M. Dubina, J.E. Craig, N. Yoshimura, P. Sundaresan, S.W.M. John, R. Ritch, M.A. Hauser, C.-C. Khor

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© 2015 Nature America, Inc. All rights reserved. Exfoliation syndrome (XFS) is the most common recognizable cause of open-angle glaucoma worldwide. To better understand the etiology of XFS, we conducted a genome-wide association study (GWAS) of 1,484 cases and 1,188 controls from Japan and followed up the most significant findings in a further 6,901 cases and 20,727 controls from 17 countries across 6 continents. We discovered a genome-wide significant association between a new locus (CACNA1A rs4926244) and increased susceptibility to XFS (odds ratio (OR) = 1.16, P = 3.36 × 10 â '11). Although we also confirmed overwhelming association at the LOXL1 locus, the key SNP marker (LOXL1 rs4886776) demonstrated allelic reversal depending on the ancestry group (Japanese: OR A allele = 9.87, P = 2.13 × 10-217; non-Japanese: OR A allele = 0.49, P = 2.35 × 10-31). Our findings represent the first genetic locus outside of LOXL1 surpassing genome-wide significance for XFS and provide insight into the biology and pathogenesis of the disease.
Original languageEnglish
Pages (from-to)387-392
JournalNature Genetics
Issue number4
Publication statusPublished - 2015


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