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)

1 SERI - Singapore Eye Research Institute [Singapore]
2 Ozaki Eye Hospital [Miyazaki]
3 FAU - Friedrich-Alexander Universität Erlangen-Nürnberg = University of Erlangen-Nuremberg
4 deCODE genetics [Reykjavik]
5 Mizoguchi Eye Hospital [Sasebo]
6 Case Western Reserve University [Cleveland]
7 Aravind Eye Hospital [Madurai, India]
8 WITS - University of the Witwatersrand [Johannesburg]
9 Pavlov First Saint Petersburg State Medical University [St. Petersburg]
10 Dalhousie University [Halifax]
11 Flinders University [Adelaide, Australia]
12 Kyoto Prefectural University of Medicine [Kyoto, Japon]
13 KSU - King Saud University [Riyadh]
14 GIS - Genome Institute of Singapore
15 AMRF - Aravind Medical Research Foundation
16 Université de Médecine Carol Davila
17 HMS - Harvard Medical School [Boston]
18 University of Washington [Seattle]
19 Hayashi Eye Hospital [Fukuoka]
20 Shinjo Eye Clinic [Nagoya]
21 Medical University of Lublin
22 Inoue Eye Hospital [Tokyo]
23 Hacettepe University = Hacettepe Üniversitesi
24 Universidad de Oviedo [Oviedo]
25 KU - Kanazawa University
26 Department of Medical and Clinical Genetics [Helsinki]
27 OMI BUENOS AIRES - Organizacion Medica de Investigacion
28 Fundacion para el Estudio del Glaucoma [Buenos Aires]
29 Chercheur indépendant
30 Eskisehir Osmangazi University
31 Ufa Eye Research Institute [Bashkortostan]
32 Seoul National University Hospital
33 Yeungnam University [South Korea]
34 Kyoto University
35 UNAM - Universidad Nacional Autónoma de México = National Autonomous University of Mexico
36 Universität Heidelberg [Heidelberg] = Heidelberg University
37 BISR - Birla Institute of Scientific Research
38 Faculty of Computer Science
39 Department of Pathology and Immunology
40 Key Laboratory for Information System Security
41 NACHOS - Numerical modeling and high performance computing for evolution problems in complex domains and heterogeneous media
42 CHU Angers - Centre Hospitalier Universitaire d'Angers
43 Institute of Human Genetics [Erlangen, Allemagne]
44 Department of Ophthalmology, School of Medicine [Thessaloniki, Grèce]
45 Aristotle University of Thessaloniki
46 UNISI - Università degli Studi di Siena = University of Siena
47 Department of Medicine, Surgery, and Dentistry
48 JAIST - Japan Advanced Institute of Science and Technology
49 Etudes génomiques trans-ethniques des maladies multifactorielles
50 Fondation Ophtalmologique Adolphe de Rothschild [Paris]
51 Archaeogenetics Laboratory
52 Génétique fonctionnelle des Maladies infectieuses - Functional Genetics of Infectious Diseases
53 Rheinische Friedrich-Wilhelms-Universität Bonn
54 UK - University of Kentucky
55 Helsinki University Eye Hospital; Turku University Hospital, Turku, Finland
56 CIIT - COMSATS Institute of Information Technology
57 Department of Epidemiology
58 UMMSM - University of Miami Leonard M. Miller School of Medicine
59 Brigham and Women's Hospital [Boston]
60 Department of Neuroscience and Pharmacology, Section of Eye Pathology, University of Copenhagen
61 Helsingin yliopisto = Helsingfors universitet = University of Helsinki
62 UC San Diego - University of California [San Diego]
63 University of Iceland [Reykjavik]
64 NYEE - New York Eye and Ear Infirmary of Mount Sinai [New York]
65 Oita University Faculty of Medicine [Oita, Japon]
66 Radboud University Medical Center [Nijmegen]

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.

Domaines: Bio-informatique [q-bio.QM]; Bio-Informatique, Biologie Systémique [q-bio.QM]; Génétique humaine; Génétique des populations [q-bio.PE]; Virologie; Parasitologie; Santé publique et épidémiologie

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⟩