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

Tin Aung, Mineo Ozaki, Takanori Mizoguchi, R Rand Allingham, Zheng Li, Aravind Haripriya, Satoko Nakano, Steffen Uebe, Jeffrey M Harder, Anita S Y Chan, Mei Chin Lee, Kathryn P Burdon, Yury S Astakhov, Khaled K Abu-Amero, Juan C Zenteno, Yildirim Nilgün, Tomasz Zarnowski, Mohammad Pakravan, Leen Abu Safieh, Liyun Jia, Ya Xing Wang, Susan Williams, Daniela Paoli, Patricio G Schlottmann, Lulin Huang, Kar Seng Sim, Jia Nee Foo, Masakazu Nakano, Yoko Ikeda, Rajesh S Kumar, Morio Ueno, Shin-ichi Manabe, Ken Hayashi, Shigeyasu Kazama, Ryuichi Ideta, Yosai Mori, Kazunori 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 Y Astakhov, Essam A Osman, Saleh A Al-Obeidan, Ohoud Owaidhah, Leyla Al-Jasim, Sami Al Shahwan, Rhys A Fogarty, Paul Leo, Yaz Yetkin, Çilingir Oğuz, Mozhgan Rezaei Kanavi, Afsaneh Naderi Beni, Shahin Yazdani, Evgeny L Akopov, Kai-Yee Toh, Gareth R Howell, Andrew C Orr, Yufen Goh, Wee Yang Meah, Su Qin Peh, Ewa Kosior-Jarecka, Urszula Lukasik, Mandy Krumbiegel, Eranga N Vithana, Tien Yin Wong, Yutao Liu, Allison E Ashley Koch, Pratap Challa, Robyn M Rautenbach, David A Mackey, Alex W 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 A Perera, Rahat Husain, Su-Ling Ho, Ulrich-Christoph Welge-Luessen, Christian Mardin, Ursula Schloetzer-Schrehardt, Axel M Hillmer, Stefan Herms, Susanne Moebus, Markus M Nöthen, Nicole Weisschuh, Rohit Shetty, Arkasubhra Ghosh, Yik Ying Teo, Matthew A Brown, Ignacio Lischinsky, Jonathan G Crowston, Michael Coote, Bowen Zhao, Jinghong Sang, Nihong Zhang, Qisheng You, Vera Vysochinskaya, Panayiota Founti, Anthoula Chatzikyriakidou, Alexandros Lambropoulos, Eleftherios Anastasopoulos, Anne L Coleman, M Roy Wilson, Douglas J Rhee, Jae Hee Kang, Inna May-Bolchakova, Steffen Heegaard, Kazuhiko Mori, Wallace L M Alward, Jost B Jonas, Liang Xu, Jeffrey M Liebmann, Balram Chowbay, Elke Schaeffeler, Matthias Schwab, Fabian Lerner, Ningli Wang, Zhenglin Yang, Paolo Frezzotti, Shigeru Kinoshita, John H Fingert, Masaru Inatani, Kei Tashiro, André Reis, Deepak P Edward, Louis R Pasquale, Toshiaki Kubota, Janey L Wiggs, Francesca Pasutto, Fotis Topouzis, Michael Dubina, Jamie E Craig, Nagahisa Yoshimura, Periasamy Sundaresan, Simon W M John, Robert Ritch, Michael A Hauser, Chiea-Chuen Khor

doi:10.1038/ng.3226

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(-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.

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

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