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

Tin Aung; Mineo Ozaki; Mei Chin Lee; Ursula Schlötzer-Schrehardt; Gudmar Thorleifsson; Takanori Mizoguchi; Robert Igo; Aravind Haripriya; Susan Williams; Yury Astakhov; Andrew Orr; Kathryn Burdon; Satoko Nakano; Kazuhiko Mori; Khaled Abu-Amero; Michael Hauser; Zheng Li; Gopalakrishnan Prakadeeswari; Jessica Bailey; Alina Popa Cherecheanu; Jae Kang; Sarah Nelson; Ken Hayashi; Shin-Ichi Manabe; Shigeyasu Kazama; Tomasz Zarnowski; Ken Inoue; Murat Irkec; Miguel Coca-Prados; Kazuhisa Sugiyama; Irma Järvelä; Patricio Schlottmann; S. Fabian Lerner; Hasnaa Lamari; Yildirim Nilgün; Mukharram Bikbov; Ki Ho Park; Soon Cheol Cha; Ken Yamashiro; Juan Zenteno; Jost Jonas; Rajesh Kumar; 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; Karen Bedard; Wenda Greer; Zheng Yang; Xueyi Chen; Lulin Huang; Jinghong Sang; Hongyan Jia; Liyun Li; Chunyan Qiao; Hui Zhang; Xuyang Li; Bowen Zhao; Ya-Xing Wang; Liang Li; Stéphanie Leruez; Pascal Reynier; George Chichua; Sergo Tabagari; Steffen Uebe; Matthias Zenkel; Daniel Berner; Georg Mossböck; Nicole Weisschuh; Ursula Hoja; Ulrich-Christoph Welge-Luessen; Christian Mardin; Panayiota Founti; Anthi Cha; Theofanis Pappas; Eleftherios Anastasopoulos; 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; Saleh Al Obeidan

doi:10.1038/ng.3875

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

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

Tin Aung, Mineo Ozaki, Mei Chin Lee, Ursula Schlötzer-Schrehardt, Gudmar Thorleifsson, Takanori Mizoguchi, Robert Igo, Aravind Haripriya, Susan Williams, Yury Astakhov, …

Nature genetics, Vol.49(7), pp.993-1004

01/07/2017

DOI: https://doi.org/10.1038/ng.3875

PMCID: PMC6685441

PMID: 28553957

Abstract

Bioinformatics

Computer Science

Genetics

Human genetics

Life Sciences

Microbiology and Parasitology

Parasitology

Populations and Evolution

Quantitative Methods

Santé publique et épidémiologie

Virology

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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Title: Genetic association study of exfoliation syndrome identifies a protective rare variant at LOXL1 and five new susceptibility loci
Creators - without role: Tin Aung - Singapore Eye Research Institute
Mineo Ozaki - Miyata Eye Hospital
Mei Chin Lee - Singapore Eye Research Institute
Ursula Schlötzer-Schrehardt - Universitätsklinikum Erlangen
Gudmar Thorleifsson - deCODE Genetics
Takanori Mizoguchi - Mizoguchi Eye Hospital [Sasebo]
Robert Igo - Case Western Reserve University
Aravind Haripriya - Aravind Eye Hospital
Susan Williams - University of the Witwatersrand
Yury Astakhov - First Pavlov State Medical University of St. Petersburg
Andrew Orr - Dalhousie University
Kathryn Burdon - University of Tasmania
Satoko Nakano - Kyoto Prefectural University of Medicine
Kazuhiko Mori - Kyoto Prefectural University of Medicine
Khaled Abu-Amero - King Saud University
Michael Hauser - Duke University
Zheng Li - Genome Institute of Singapore
Gopalakrishnan Prakadeeswari - Aravind Medical Research Foundation
Jessica Bailey - Case Western Reserve University
Alina Popa Cherecheanu - Université de Médecine Carol Davila
Jae Kang - Brigham and Women's Hospital
Sarah Nelson - University of Washington
Ken Hayashi - Hayashi Eye Hospital
Shin-Ichi Manabe - Hayashi Eye Hospital
Shigeyasu Kazama - Miyata Eye Hospital
Tomasz Zarnowski - Medical University of Lublin
Ken Inoue - Inoue Eye Hospital [Tokyo]
Murat Irkec - Hacettepe University
Miguel Coca-Prados - Fernández-Vega Ophthalmological Institute
Kazuhisa Sugiyama - Kanazawa University
Irma Järvelä - University of Helsinki
Patricio Schlottmann - Organizacion Medica de Investigacion
S. Fabian Lerner - Fundacion para el Estudio del Glaucoma [Buenos Aires]
Hasnaa Lamari - École Normale Supérieure de l'Enseignement Technique de Mohammedia
Yildirim Nilgün - Eskişehir Osmangazi University
Mukharram Bikbov - Ufa Eye Research Institute
Ki Ho Park - Seoul National University Hospital
Soon Cheol Cha - Yeungnam University
Ken Yamashiro - Kyoto University
Juan Zenteno - Institute of Ophthalmology
Jost Jonas - Heidelberg University
Rajesh Kumar - Narayana Nethralaya
Shamira Perera - Singapore Eye Research Institute
Anita Cha
Nino Kobakhidze
Ronnie George - India Diabetes Research Foundation
Lingam Li
Tan Do
Deepak Edward - King Khaled Eye Specialist Hospital
Juan de Juan Marcos
Mohammad Pakravan - Shahid Beheshti University of Medical Sciences
Sasan Moghimi - Farabi Eye Hospital
Ryuichi Ideta - Ideta Eye Hospital
Daniella Bach-Holm - Glostrup Hospital
Per Kappelgaard - Glostrup Hospital
Barbara Wirostko - University of Utah
Samuel Thomas - University of Utah
Daniel Gaston - Dalhousie University
Karen Bedard - Dalhousie University
Wenda Greer - Dalhousie University
Zheng Yang
Xueyi Chen - First Affiliated Hospital of Xinjiang Medical University
Lulin Huang - Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital
Jinghong Sang - Capital Medical University
Hongyan Jia - Beijing Tongren Hospital
Liyun Li
Chunyan Qiao - Beijing Tongren Hospital
Hui Zhang - Beijing Tongren Hospital
Xuyang Li
Bowen Zhao - Beijing Tongren Hospital
Ya-Xing Wang
Liang Li - Numerical modeling and high performance computing for evolution problems in complex domains and heterogeneous media
Stéphanie Leruez - Centre Hospitalier Universitaire d'Angers
Pascal Reynier - Centre Hospitalier Universitaire d'Angers
George Chichua
Sergo Tabagari - David Tvildiani Medical University
Steffen Uebe - Friedrich-Alexander-Universität Erlangen-Nürnberg
Matthias Zenkel - Universitätsklinikum Erlangen
Daniel Berner - Universitätsklinikum Erlangen
Georg Mossböck - Medical University of Graz
Nicole Weisschuh - STZ eyetrial
Ursula Hoja - Universitätsklinikum Erlangen
Ulrich-Christoph Welge-Luessen - Universitätsklinikum Erlangen
Christian Mardin - Universitätsklinikum Erlangen
Panayiota Founti - Aristotle University of Thessaloniki
Anthi Cha
Theofanis Pappas - Aristotle University of Thessaloniki
Eleftherios Anastasopoulos - Aristotle University of Thessaloniki
Alexandros Lambropoulos - Aristotle University of Thessaloniki
Arkasubhra Ghosh - Narayana Nethralaya
Rohit Shetty - Narayana Nethralaya
Natalia Porporato - Hospital Británico de Buenos Aires
Vijayan Vijaya
Rengaraj Venkatesh - Aravind Eye Hospital
Chandrashekaran Cha
Narendran Kalpana
Sripriya Sarangapani
Mozhgan Kanavi - Shahid Beheshti University of Medical Sciences
Afsaneh Naderi Beni - Shahid Beheshti University of Medical Sciences
Shahin Yazdani - Shahid Beheshti University of Medical Sciences
Saleh Al Obeidan - King Saud University
Publication Details: Nature genetics, Vol.49(7), pp.993-1004
Publisher: Nature Publishing Group
Identifiers: 9948540608331
Academic Unit: King Saud University
Language: English
Resource Type: Journal article