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

Tin Aung, Ozaki Mineo, Takanori Mizoguchi, R Allingham, Zheng Li, Aravind Haripriya, Satoko Nakono, Steffen Uebe, Jeffrey Harder, Anita Chan, Mei Lee, Kathryn Burdon, Yury Astakhov, Khalid Abu-Amero, Juan Zenteno, Yildirim Nilgun, Tomasz Zarnowski, Mohammad Pakravan, Leen Safieh, Liyun JiaYa Xing Wang, Susan Williams, Daniela Paoli, Patricio Schlottmann, Lulin Huang, Kar-Seng Sim, Jia-Nee Foo, Masakazu Nakano, Yoko Ikeda, Rajesh Kumar, Morio Ueno, Shin-ichi Manabe, Kenshi Hayashi, Shigeyasu Kazama, Ryuichi Ideta, Yosai Mori, K Miyata, Kazuhisa Sugiyama, Tomomi Higashide, Etsuo Chihara, Kenji Inoue, Satoshi Ishiko, Akitoshi Yoshida, Masahide Yanagi, Yoshiaki Kiuchi, Makoto Aihara, Tsutomu Ohashi, Toshiya Sakurai, Takako Sugimoto, Hideki Chuman, Fumihiko Matsuda, Kenji Yamashiro, Norimoto Gotoh, Masahiro Miyake, Sergei Astakhov, Essam Osman, Saleh Al-Obeidan, Ohoud Owaidhah, Leyla Al-Jasim, Sami Al Shahwan, Rhys Fogarty, Paul Leo, Yaz Yetkin, Cilingir Oguz, Mozhgan Kanavi, Afsaneh Beni, Shahin Yazdani, Evgeny Akopov, Kai-Yee Toh, Gareth Howell, Andrew Orr, Yufen Goh, Wee Meah, Su Qin Peh, Ewa Kosior-Jarecka, Urszula Lukasik, Mandy Krumbiegel, Eranga Vithana, Tien Wong, Yutao Liu, Allison Ashely-Koch, Pratap Challa, Robyn Rautenbach, David Mackey, Alex Hewitt, Paul Mitchell, Jie Jin Wang, Ari Ziskind, Trevor Carmichael, Rangappa Ramakrishnan, Kalpana Narendran, Rangaraj Venkatesh, Saravanan Vijayan, Peiquan Zhao, Xueyi Chen, Dalia Guadarrama-Vallejo, Ching Yu Cheng, Shamira Perera, Rahat Husain, Su-Ling Ho, Ulrich-Christoph Welge-Luessen, Christian Mardin, Ursula Schloetzer-Schrehardt, Axel Hillmer, Stefan Herms, Susanne Moebus, Markus Nothen, Nicole Weisschuh, Rohit Shetty, Arkasubhra Ghosh, Yik-Ying Teo, Matthew Brown, Ignacio Lischinsky, Jonathan Crowston, Michelle Coote, Bowen Zhao, Jinghong Sang, NiHong Zhang, Qisheng You, Vera Vysochinskaya, Panayiota Founti, Anthoula Chatzikyriakidou, Alexandros Lambropoulos, Eleftherios Anastasopoulos, Anne Coleman, Wilson M, Douglas Rhee, Jae Kang, Inna May-Bolchakova, Steffen Heegaard, Kazuhiko Mori, Wallace Alward, Jost Jonas, Liang Xu, Jeffrey Liebmann, Balram Chowbay, Elke Schaeffeler, Matthias Schwab, Fabian Lerner, Ningli Wang, Zhenglin Yang, Paolo Frezzotti, Shigeru Kinoshita, John Fingert, Masaru Inatani, Kei Tashiro, Andre Reis, Deepak Edward, Louis Pasquale, Toshiaki Kubota, Janey Wiggs, Francesca Pasutto, Fotis Topouzis, Michael Dubina, Jamie Craig, Nagahisa Yoshimura, Periasamy Sundaresan, Simon John, Robert Ritch, Michael Hauser, Chiea-Chuen Khor

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Abstract

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
Number of pages6
JournalNature Genetics
Volume47
Issue number4
DOIs
Publication statusPublished - 28 Apr 2015

Keywords

  • Exfoliation syndrome
  • open-angle glaucoma
  • genome-wide association study

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    Aung, T., Mineo, O., Mizoguchi, T., Allingham, R., Li, Z., Haripriya, A., Nakono, S., Uebe, S., Harder, J., Chan, A., Lee, M., Burdon, K., Astakhov, Y., Abu-Amero, K., Zenteno, J., Nilgun, Y., Zarnowski, T., Pakravan, M., Safieh, L., ... Khor, C-C. (2015). A common variant mapping to CACNA1A is associated with susceptibility to exfoliation syndrome. Nature Genetics, 47(4), 387-392. https://doi.org/10.1038/ng.3226, https://doi.org/10.1038/ng0615-689c