Genetic association study of exfoliation syndrome identifies a protective rare variant at LOXL1 and five new susceptibility loci

Tin Aung, Mineo Ozaki, Mei Lee, Ursula Schloetzer-Schrehardt, G Thorleifsson, Takanori Mizoguchi, Robert Igo, Aravind Haripriya, Susan Williams, Yury Astakhov, Andrew Orr, Kathryn Burdon, Satoko Nakano, Kazuhiko Mori, Khalid Abu-Amero, Michael Hauser, Zheng Li, Gopalakrishnan Prakadeeswari, Jessica Bailey, Alina CherecheanuJae Kang, Sarah Nelson, Ken Hayashi, Shin-ichi Manabe, Shigeyasu Kazama, Tomasz Zarnowski, Kenji Inoue, Murat Irkec, Miguel Coca-Prados, Kazuhisa Sugiyama, Irma Jarvela, Patricio Schlottmann, Fabian Lerner, Hasnaa Lamari, Yildirim Nilgun, Mukharram Bikbov, Ki-Ho Park, Soon Cha, Kenji Yamashiro, Juan Zenteno, Jost Jonas, Rajesh Kumar, Shamira Perera, Anita Chan, Nino Kobakhidze, Ronnie George, Lingam Vijaya, Tan Do, Deepak Edward, Lourdes de Juan Marcos, Mohammad Pakravan, Sasan Moghimi, Ryuichi Ideta, Daniella Bach-Holme, Per Kappelgaard, Barbara Wirostko, Samual Thomas, Daniel Gaston, Karen Bedard, Wenda Greer, Zhenglin Yang, Xueyi Chen, Lulin Huang, Jinghong Sang, Hongyan Jia, Liyun Jia, Chunyan Qiao, Hui Zhang, Xuyang Liu, Bowen Zhao, Yaxing Wang, Liang Xu, Stephanie Leruez, Pascal Reynier, George Chichua, Sergo Tabagari, Steffen Uebe, Matthias Zenkel, Daniel Berner, Georg Mossbock, Nicole Weisschuh, Ursula Hoja, Ulrich-Christoph Welge-Luessen, Christian Mardin, Panayiota Founti, Anthoula Chatzikyriakidou, Theofanis Pappas, Eleftherios Anastasopoulos, Alexandros Lambropoulos, Arkasubhra Ghosh, Rohit Shetty, Natalia Porporato, Vijayan Saravanan, Rangaraj Venkatesh, Chandrashekaran Shivkumar, Narendran Kalpana, Sripriya Sarangapani, Mozhgan Kanavi, Afsaneh Beni, Shahin Yazdani, Alireza Lashay, Homa Naderifar, Nassim Khatibi, Antonio Fea, Carlo Lavia, Laura Dallorto, Teresa Rolle, Paolo Frezzotti, Daniela Paoli, Erika Salvi, Paolo Manunta, Yosai Mori, K Miyata, Tomomi Higashide, Etsuo Chihara, Satoshi Ishiko, Akitoshi Yoshida, Yoshiaki Kiuchi, Masahide Yanagi, Tsutomu Ohashi, Toshiya Sakurai, Takako Sugimoto, Hideki Chuman, Makoto Aihara, Masaru Inatani, Masahiro Miyake, Norimoto Gotoh, Fumihiko Matsuda, Nagahisa Yoshimura, Yoko Ikeda, Morio Ueno, Chie Sotozono, Jin Jeoung, Min Sagong, Kyu Park, Jeeyun Ahn, Marisa Cruz-Aguilar, Sidi Ezzouhairi, Abderrahman Rafei, Yaan Chong, Xiao Ng, Shuang Goh, Yueming Chen, Victor Yong, Muhammad Khan, Olusola Olawoye, Adeyinka Ashaye, Idakwo Ugbede, Adeola Onakoya, Nkiru Kizor-Akaraiwe, Chaiwat Teekhasaenee, Yanin Suwan, Wasu Supakontanasan, Suhanya Okeke, Nkechi Uche, Ifeoma Asimadu, Humaira Ayub, Farah Akhtar, Ewa Kosior-Jarecka, Urszula Lukasik, Ignacio Lischinsky, Vania Castro, Rodolfo Perez-Grossmann, Gordana Sunaric Megevand, Sylvain Roy, Edward Dervan, Eoin Silke, Aparna Rao, Priti Sahay, Pablo Fornero, Osvaldo Cuello, Delia Sivori, Tamara Zompa, Richard Mills, Emmanuelle Souzeau, Paul Mitchell, Jie Jin Wang, Alex Hewitt, Michael Coote, Jonathan Crowston, Sergei Astakhov, Evgeny Akopov, Anton Emelyanov, Vera Vysochinskaya, Gyulli Kazakbaeva, Rinat Fayzrakhmanov, Saleh Al-Obeidan, Ohoud Owaidhah, Leyla Aljasim, Balram Chowbay, Jia-Nee Foo, Raphael Soh, Kar-Seng Sim, Zhicheng Xie, Augustine Cheong, Shi Mok, Hui Soo, Xiao Chen, Su Qin Peh, Khai Heng, Rahat Husain, Su-Ling Ho, Axel Hillmer, Ching-Yu Cheng, Francisco Escudero-Domínguez, Rogelio González-Sarmiento, Frederico Martinon-Torres, Antonio Salas, Kessara Pathanapitoon, Linda Hansapinyo, Boonsong Wanichwecharugruang, Naris Kitnarong, Anavaj Sakuntabhai, Hip Nguyn, Giang Nguyn, Trinh Nguyn, Werner Zenz, Alexander Binder, Daniela Klobassa, Martin Hibberd, S. Davila, Stefan Herms, Markus Nothen, Susanne Moebus, Robyn Rautenbach, Ari Ziskind, Trevor Carmichael, Michele Ramsay, Lydia Alvarez, Montserrat Garcia, Hector González-Iglesias, Pedro Rodríguez-Calvo, Luis Fernández-Vega Cueto, Cilingir Oguz, Nevbahar Tamcelik, Eray Atalay, Bilge Batu, Dilek Aktas, Burcu Kasim, Roy Wilson, Anne Coleman, Yutao Liu, Pratap Challa, Leon Herndon, Rachel Kuchtey, John Kuchtey, Karen Curtin, Craig Chaya, Alan Crandall, Linda Zangwill, Tien Wong, Masakazu Nakano, Shigeru Kinoshita, Anneke den Hollander, Eija Vesti, John Fingert, Richard Lee, Arthur Sit, Bradford Shingleton, Ningli Wang, Daniele Cusi, Raheel Qamar, Peter Kraft, Margaret Pericak-Vance, S Raychaudhuri, Steffen Heegaard, Tero Kivela, Andre Reis, Friedrich Kruse, Robert Weinreb, Louis Pasquale, Jonathan Haines, Unnur Thorsteinsdottir, Fridbert Jonasson, R Allingham, Dan Milea, Robert Ritch, Toshiaki Kubota, Kei Tashiro, Eranga Vithana, Shazia Michael, Fotis Topouzis, Jamie Craig, Michael Dubina, Periasamy Sundaresan, K Stefansson, Janey Wiggs, Francesca Pasutto, Chiea-Chuen Khor

Research output: Contribution to journalArticlepeer-review

43 Citations (Scopus)

Abstract

Exfoliation syndrome (XFS) is the most common known risk factor for secondary glaucoma and a major cause of blindness worldwide. Variants in two genes, LOXL1 and CACNA1A, have previously been associated with XFS. To further elucidate the genetic basis of XFS, we collected a global sample of XFS cases to refine the association at LOXL1, which previously showed inconsistent results across populations, and to identify new variants associated with XFS. We identified a rare protective allele at LOXL1 (p.Phe407, odds ratio (OR) = 25, P = 2.9 × 10-14) through deep resequencing of XFS cases and controls from nine countries. A genome-wide association study (GWAS) of XFS cases and controls from 24 countries followed by replication in 18 countries identified seven genome-wide significant loci (P < 5 × 10-8). We identified association signals at 13q12 (POMP), 11q23.3 (TMEM136), 6p21 (AGPAT1), 3p24 (RBMS3) and 5q23 (near SEMA6A). These findings provide biological insights into the pathology of XFS and highlight a potential role for naturally occurring rare LOXL1 variants in disease biology.

Original languageEnglish
Pages (from-to)993-1004
Number of pages12
JournalNature Genetics
Volume49
Issue number7
DOIs
Publication statusPublished - 1 Jul 2017

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