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

Tin P Aung 1 Mineo Ozaki 2 Mei Chin Lee 1 Ursula Schlötzer-Schrehardt 3 Gudmar Thorleifsson 4 Takanori Mizoguchi 5 Robert Igo 6 Aravind Haripriya 7 Susan Williams 8 Yury Astakhov 9 Andrew Orr 10 Kathryn Burdon 11 Satoko Nakano 12 Kazuhiko Mori 12 Khaled Abu-Amero 13 Michael Hauser 1 Zheng Li 14 Gopalakrishnan Prakadeeswari 15 Jessica Bailey 6 Alina Popa Cherecheanu 16 Jae H. Kang 17 Sarah Nelson 18 Ken Hayashi 19 Shin-Ichi Manabe 19 Shigeyasu Kazama 20 Tomasz Zarnowski 21 Ken Inoue 22 Murat Irkec 23 Miguel Coca-Prados 24 Kazuhisa Sugiyama 25 Irma Järvelä 26 Patricio Schlottmann 27 S. Fabian Lerner 28 Hasnaa Lamari 29 Yildirim Nilgün 30 Mukharram Bikbov 31 Ki Ho Park 32 Soon Cheol Cha 33 Ken Yamashiro 34 Juan Zenteno 35 Jost Jonas 36 Rajesh Kumar 37 Shamira Perera Anita Cha Nino Kobakhidze Ronnie George Lingam Li Tan Do Deepak Edward Juan de Juan Marcos Mohammad Pakravan Sasan Moghimi Ryuichi Ideta Daniella Bach-Holm Per Kappelgaard Barbara Wirostko Samuel Thomas Daniel Gaston 38 Karen Bedard 39 Wenda Greer Zheng Yang Xueyi Chen Lulin Huang Jinghong Sang Hongyan Jia Liyun Li Chunyan Qiao Hui Zhang 40 Xuyang Li Bowen Zhao Ya-Xing Wang Liang Li 41 Stéphanie Leruez 42 Pascal Reynier 42 George Chichua Sergo Tabagari Steffen Uebe 43 Matthias Zenkel 43 Daniel Berner Georg Mossböck Nicole Weisschuh 43 Ursula Hoja Ulrich-Christoph Welge-Luessen Christian Mardin Panayiota Founti 44 Anthi Cha Theofanis Pappas Eleftherios Anastasopoulos 45 Alexandros Lambropoulos Arkasubhra Ghosh Rohit Shetty Natalia Porporato Vijayan Vijaya Rengaraj Venkatesh Chandrashekaran Cha Narendran Kalpana Sripriya Sarangapani Mozhgan Kanavi Afsaneh Naderi Beni Shahin Yazdani Alireza Lashay Homa Naderifar Nassim Khatibi Antonio Fea Carlo Lavia Laura Dallorto Teresa Rolle Paolo Frezzotti 46 Daniel Paoli Erika Salvi 47 Paolo Manunta Yosai Mori Kazunori Miyata 48 Tomomi Higashide Etsuo Chihara Satoshi Ishiko Akitoshi Yoshida Masahide Yanagi Yoshiaki Kiuchi Tsutomu Ohashi Toshiya Sakurai Takako Sugimoto Hideki Chuman Makoto Aihara Masaru Inatani Masahiro Miyake Norimoto Gotoh Fumihiko Matsuda 49 Nagahisa Yoshimura Yoko Ikeda Morio Mori Chie Sotozono Jin Wook Jeoung Min Sagong Kyu Hyung Park Jeeyun Ahn Marisa Cruz-Aguilar Sidi Ezzouhairi Abderrahman Rafei Yaan Fun Chong Xiao Yu Ng Shuang Ru Goh Yueming Chen Victor Yong Muhammad Imran Khan Olusola Olawoye Adeyinka Ashaye Idakwo Ugbede Adeola Onakoya Nkiru Kizor-Akaraiwe Chaiwat Cha Yanin Suwan Wasu Supakontanasan Suhanya Okeke Nkechi Uche Ifeoma Asimadu Humaira Ayub Farah Akhtar Ewa Kosior-Jarecka Urszula Lukasik Ignacio Li Vania Castro Per Grossmann Gordana Sunaric Megevand 50 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 Eugeny Akopov Anton Emelyanov Vera Vysochinskaya Gyulli Kazakbaeva Rinat Fayzrakhmanov Saleh Al-Obeidan Ohoud Owaidhah Leyla Ali Aljasim Balram Chowbay Jia Nee Jia Raphael Soh Kar Seng Sim Zhicheng Xie Augustine Cheong Shi Qi Mok Hui Soo Xiao Yin Chen Su Qin Peh Khai Koon Heng Rahat Husain Su-Ling Li Axel Hillmer Ching-Yu Chen Francisco Do Rogelio González-Sarmiento Frederico Martinon-Torres Antonio Salas 51 Kessara Pathanapitoon Boonsong Wanichwecharugruang Naris Kitnarong Anavaj Sakuntabhai 52 Hip Ng Giang Ng Trình Ng Werner Zenz Alex Binder Daniel Klobassa Martin L Hibberd 14 Sonia Davila Stefan Herms 53 Markus Nöthen 43 Susan Moebus Robyn Rautenbach Ari Ziskind Trevor Carmichael Michele Ramsay Lydia Álvarez Montserrat García Héctor González-Iglesias Pedro Rodríguez-Calvo Luis Fernández-Vega Cueto Çilingir Oguz Nevbahar Tamcelik Eray Atalay Bilge Batu Dilek Aktas Burcu Kasim Anne Coleman Yutao Li Pratap Cha Leon Herndon Rachel Kuchtey John Kuchtey Karen Curtin Craig Cha Alan Crandall Linda Li 54 Tien Yin Wong Masakazu Nakano Shigeru Kinoshita Anne Ho Eija Vesti 55 John Fingert Richard Lee Arthur Sit Bradford Shingleton Ningli Wang Daniel Cusi Raheel Qamar 56 Peter Kraft 57 Margaret Pericak-Vance 58 Soumya Raychaudhuri 59 Steffen Heegaard 60 Tero Kivelä 61 André Reis 3 Friedrich Kruse 3 Robert Weinreb 62 Louis Pasquale 17 Jonathan L. Haines 6 Unnur Thorsteinsdóttir 63 Fridbert Jonasson 63 R Rand Allingham 1 Dan Milea 1 Robert Ritch 64 Toshiaki Kubota 65 Kei Tashiro 12 Eranga Vithana 1 Shazia Micheal 66 Fotis Topouzis 45 Jamie E Craig 11 Michael Dubina 9 Per Sundaresan 7 Stefan Stefansson 4 Janey Wiggs 17 Francesca Pasutto 43 Chiea Chuen Khor 1 
41 NACHOS - Numerical modeling and high performance computing for evolution problems in complex domains and heterogeneous media
CRISAM - Inria Sophia Antipolis - Méditerranée , JAD - Laboratoire Jean Alexandre Dieudonné : UMR6621
Abstract : Exfoliation syndrome (XFS) is the commonest known risk factor for secondary glaucoma and a significant cause of blindness worldwide. Variants in two genes, LOXL1 and CACNA1A have been previously 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 between populations,and to identify new variants associated with XFS. We identified a rare, protective allele at LOXL1 (p.407Phe, OR= 25, P=2.9 x 10-14) through deep resequencing of XFS cases and controls from 9 countries. This variant results in increased cellular adhesion strength compared to the wild-type (p.407Tyr) allele. 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 x 10-8). Index variants at the new loci map to chromosomes 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.
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Tin P Aung, Mineo Ozaki, Mei Chin Lee, Ursula Schlötzer-Schrehardt, Gudmar Thorleifsson, et al.. Genetic association study of exfoliation syndrome identifies a protective rare variant at LOXL1 and five new susceptibility loci. Nature Genetics, 2017, 49 (7), pp.993-1004. ⟨10.1038/ng.3875⟩. ⟨pasteur-02003892⟩

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