Journal article
A common variant mapping to CACNA1A is associated with susceptibility to exfoliation syndrome
Nature genetics, Vol.47(4), pp.387-392
04/2015
DOI: 10.1038/ng.3226
PMCID: PMC4605818
PMID: 25706626
Abstract
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.
Details
- Title: Subtitle
- A common variant mapping to CACNA1A is associated with susceptibility to exfoliation syndrome
- Creators
- Satoshi Ishiko - Department of Medicine and Engineering Combined Research Institute, Asahikawa Medical University, Asahikawa, JapanAkitoshi Yoshida - Department of Ophthalmology, Asahikawa Medical University, Asahikawa, JapanMasahide Yanagi - Department of Ophthalmology and Visual Science, Hiroshima University, Hiroshima, JapanYoshiaki Kiuchi - Department of Ophthalmology and Visual Science, Hiroshima University, Hiroshima, JapanMakoto Aihara - Yotsuya Shirato Eye Clinic, Tokyo, JapanTsutomu Ohashi - Ohashi Eye Center, Sapporo, JapanToshiya Sakurai - Tane Memorial Eye Hospital, Osaka, JapanTakako Sugimoto - Department of Ophthalmology, Faculty of Medicine, University of Miyazaki, Miyazaki, JapanHideki Chuman - Department of Ophthalmology, Faculty of Medicine, University of Miyazaki, Miyazaki, JapanFumihiko Matsuda - Center for Genomic Medicine/INSERM U852, Kyoto University Graduate School of Medicine, Kyoto, JapanKenji Yamashiro - Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Kyoto, JapanNorimoto Gotoh - Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Kyoto, JapanMasahiro Miyake - Kyoto UniversitySergei Y Astakhov - Department of Ophthalmology, First Pavlov State Medical University of St. Petersburg, St. Petersburg, RussiaEssam A Osman - Department of Ophthalmology, College of Medicine, King Saud University, Riyadh, Saudi ArabiaSaleh A Al-Obeidan - Department of Ophthalmology, College of Medicine, King Saud University, Riyadh, Saudi ArabiaOhoud Owaidhah - Department of Ophthalmology, Ophthalmic Research Center, Labbafinejad Medical Center, Shahid Beheshti University of Medical Sciences, Tehran, IranLeyla Al-Jasim - Department of Ophthalmology, Ophthalmic Research Center, Labbafinejad Medical Center, Shahid Beheshti University of Medical Sciences, Tehran, IranSami Al Shahwan - Department of Ophthalmology, Ophthalmic Research Center, Labbafinejad Medical Center, Shahid Beheshti University of Medical Sciences, Tehran, IranRhys A Fogarty - Department of Ophthalmology, Flinders University, Adelaide, South Australia, AustraliaPaul Leo - The University of QueenslandYaz Yetkin - Department of Ophthalmology, Eskisehir Osmangazi University, Meselik, TurkeyÇilingir Oğuz - Department of Ophthalmology, Eskisehir Osmangazi University, Meselik, TurkeyMozhgan Rezaei Kanavi - Department of Ophthalmology, Ophthalmic Research Center, Labbafinejad Medical Center, Shahid Beheshti University of Medical Sciences, Tehran, IranAfsaneh Nederi Beni - Department of Ophthalmology, Ophthalmic Research Center, Labbafinejad Medical Center, Shahid Beheshti University of Medical Sciences, Tehran, IranShahin Yazdani - Department of Ophthalmology, Ophthalmic Research Center, Labbafinejad Medical Center, Shahid Beheshti University of Medical Sciences, Tehran, IranEvgeny L Akopov - Department of Ophthalmology, First Pavlov State Medical University of St. Petersburg, St. Petersburg, RussiaKai-Yee Toh - Division of Human Genetics, Genome Institute of Singapore, SingaporeGareth R Howell - Howard Hughes Medical Institute, Jackson Laboratory, Bar Harbor, Maine, USAAndrew C Orr - Department of Ophthalmology and Visual Sciences, Dalhousie University, Halifax, Nova Scotia, CanadaYufen Goh - Division of Human Genetics, Genome Institute of Singapore, SingaporeWee Yang Meah - Division of Human Genetics, Genome Institute of Singapore, SingaporeSu Qin Peh - Division of Human Genetics, Genome Institute of Singapore, SingaporeEwa Kosior-Jarecka - Department of Diagnostics and Microsurgery of Glaucoma, Medical University, Lublin, PolandUrszula Lukasik - Department of Diagnostics and Microsurgery of Glaucoma, Medical University, Lublin, PolandMandy Krumbiegel - Institute of Human Genetics, Friedrich Alexander Universität Erlangen-Nürnberg, Erlangen-Nürnberg, GermanyEranga N Vithana - Singapore Eye Research Institute, SingaporeTien Yin Wong - National University of SingaporeYutao Liu - Duke UniversityAllison E Ashley Koch - Department of Medicine, Duke University Medical Center, Durham, North Carolina, USAPratap Challa - Department of Ophthalmology, Duke University Eye Center, Durham, North Carolina, USASusan Williams - Division of Ophthalmology, Department of Neurosciences, University of the Witwatersrand, Johannesburg, South AfricaDaniela Paoli - Department of Ophthalmology, Monfalcone Hospital, Gorizia, ItalyRobyn M Rautenbach - Division of Ophthalmology, Faculty of Medicine and Health Sciences, University of Stellenbosch, Cape Town, South AfricaPatricio G Schlottmann - Organización Médica de Investigación, Buenos Aires, ArgentinaDavid A Mackey - Centre for Ophthalmology and Visual Science, Lions Eye Institute, University of Western Australia, Perth, Western Australia, AustraliaLulin Huang - Sichuan Academy of Medical Sciences & Sichuan Provincial People's HospitalAlex W Hewitt - The University of MelbourneKar Seng Sim - Division of Human Genetics, Genome Institute of Singapore, SingaporePaul Mitchell - The University of SydneyJia Nee Foo - Division of Human Genetics, Genome Institute of Singapore, SingaporeJie Jin Wang - The University of SydneyMasakazu Nakano - Department of Genomic Medical Sciences, Kyoto Prefectural University of Medicine, Kyoto, JapanAri Ziskind - Division of Ophthalmology, Faculty of Medicine and Health Sciences, University of Stellenbosch, Cape Town, South AfricaYoko Ikeda - Department of Ophthalmology, Kyoto Prefectural University of Medicine, Kyoto, JapanTrevor Carmichael - Division of Ophthalmology, Department of Neurosciences, University of the Witwatersrand, Johannesburg, South AfricaRajesh S Kumar - Glaucoma Services, Narayana Nethralaya Eye Hospital, Bangalore, IndiaRangappa Ramakrishnan - Intraocular Lens and Cataract Clinic, Aravind Eye Hospital, Madurai, IndiaMorio Ueno - Department of Ophthalmology, Kyoto Prefectural University of Medicine, Kyoto, JapanKalpana Narendran - Intraocular Lens and Cataract Clinic, Aravind Eye Hospital, Madurai, IndiaRangaraj Venkatesh - Intraocular Lens and Cataract Clinic, Aravind Eye Hospital, Madurai, IndiaShin-ichi Manabe - Hayashi Eye Hospital, Fukuoka, JapanSaravanan Vijayan - Department of Genetics, Aravind Medical Research Foundation, Madurai, IndiaKen Hayashi - Hayashi Eye Hospital, Fukuoka, JapanShigeyasu Kazama - Shinjo Eye Clinic, Miyazaki, JapanPeiquan Zhao - Department of Ophthalmology, Xin Hua Hospital affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai, ChinaRyuichi Ideta - Ideta Eye Hospital, Kumamoto, JapanDalia Guadarrama-Vallejo - Universidad Nacional Autónoma de MéxicoShamira A Perera - Singapore National Eye CenterYosai Mori - Miyata Eye Hospital, Miyazaki, JapanKazunori Miyata - University of MiyazakiRahat Husain - Singapore National Eye CenterKazuhisa Sugiyama - Department of Ophthalmology and Visual Science, Kanazawa University Graduate School of Medical Science, Kanazawa University, Kanazawa, JapanSu-Ling Ho - National Healthcare Group Eye Institute, Tan Tock Seng Hospital, SingaporeUlrich-Christoph Welge-Luessen - Department of Ophthalmology, Friedrich Alexander Universität Erlangen-Nürnberg, Erlangen-Nürnberg, GermanyTomomi Higashide - Department of Ophthalmology and Visual Science, Kanazawa University Graduate School of Medical Science, Kanazawa University, Kanazawa, JapanEtsuo Chihara - Sensho-kai Eye Institute, Kyoto, JapanChristian Mardin - Department of Ophthalmology, Friedrich Alexander Universität Erlangen-Nürnberg, Erlangen-Nürnberg, GermanyKenji Inoue - Inouye Eye Hospital, Tokyo, JapanUrsula Schloetzer-Schrehardt - Department of Ophthalmology, Friedrich Alexander Universität Erlangen-Nürnberg, Erlangen-Nürnberg, GermanyAravind Haripriya - Intraocular Lens and Cataract Clinic, Aravind Eye Hospital, Madurai, IndiaTin Aung - Singapore Eye Research InstituteAxel M Hillmer - Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, SingaporeEleftherios Anastasopoulos - Aristotle University of ThessalonikiStefan Herms - University of BonnJonathan G Crowston - The University of MelbourneSusanne Moebus - Institute for Medical Informatics, Biometry and Epidemiology, University Hospital of Essen, University Duisburg-Essen, Essen, GermanyMineo Ozaki - Hayashi Eye HospitalMichael Coote - The University of MelbourneAnne L Coleman - University of California, Los AngelesInna May-Bolchakova - Department of Ophthalmology, Military Hospital Begin, Paris, FranceMarkus M Nöthen - University of BonnTakanori Mizoguchi - Mizoguchi Eye Hospital, Sasebo, JapanBowen Zhao - King Khaled Eye Specialist Hospital, Riyadh, Saudi ArabiaNicole Weisschuh - Institute for Ophthalmic Research, Department of Ophthalmology, Tübingen, GermanyRohit Shetty - Glaucoma Services, Narayana Nethralaya Eye Hospital, Bangalore, IndiaM Roy Wilson - Wayne State University, Detroit, Michigan, USASatoko Nakano - Department of Ophthalmology, Oita University Faculty of Medicine, Oita, JapanArkasubhra Ghosh - Singapore Eye Research InstituteDouglas J Rhee - Department of Ophthalmology, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts, USASteffen Heegaard - University of CopenhagenYik Ying Teo - Duke UniversityR Rand Allingham - Department of Ophthalmology, Duke University Eye Center, Durham, North Carolina, USAJinghong Sang - Capital Medical UniversityZheng Li - Division of Human Genetics, Genome Institute of Singapore, SingaporeNihong Zhang - Capital Medical UniversityMatthew A Brown - The University of QueenslandJae Hee Kang - Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USAIgnacio Lischinsky - Centro Oftalmológico Lischinsky, Tucumán, ArgentinaKazuhiko Mori - Department of Genomic Medical Sciences, Kyoto Prefectural University of Medicine, Kyoto, JapanQisheng You - Beijing Institute of Ophthalmology, Beijing Tongren Hospital, Capital University of Medical Science, Beijing, ChinaSteffen Uebe - Institute of Human Genetics, Friedrich Alexander Universität Erlangen-Nürnberg, Erlangen-Nürnberg, GermanyVera Vysochinskaya - St. Petersburg Academic University, St. Petersburg, RussiaJeffrey M Harder - Howard Hughes Medical Institute, Jackson Laboratory, Bar Harbor, Maine, USAPanayiota Founti - Aristotle University of ThessalonikiWallace L M Alward - University of Iowa, The University of Iowa Institute for Vision ResearchAnthoula Chatzikyriakidou - Aristotle University of ThessalonikiAnita S Y Chan - Singapore Eye Research InstituteAlexandros Lambropoulos - Department of Biology and Genetics, Faculty of Medicine, Aristotle University of Thessaloniki, Thessaloniki, GreeceJost B Jonas - Department of Ophthalmology, Medical Faculty Mannheim of the Ruprecht Karls University Heidelberg, Heidelberg, GermanyMei Chin Lee - Singapore Eye Research Institute, SingaporeLiang Xu - Beijing Institute of Ophthalmology, Beijing Tongren Hospital, Capital University of Medical Science, Beijing, ChinaKathryn P Burdon - Flinders UniversityJeffrey M Liebmann - New York University School of Medicine, Manhattan Eye, Ear and Throat Hospital, New York, New York, USAYury S Astakhov - Department of Ophthalmology, First Pavlov State Medical University of St. Petersburg, St. Petersburg, RussiaBalram Chowbay - Division of Medical Sciences, Humphrey Oei Institute of Cancer Research, National Cancer Centre of Singapore, SingaporeKhaled K Abu-Amero - King Saud UniversityElke Schaeffeler - Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, GermanyJuan C Zenteno - Universidad Nacional Autónoma de MéxicoMatthias Schwab - University of TübingenYildirim Nilgün - Department of Ophthalmology, Eskisehir Osmangazi University, Meselik, TurkeyFabian Lerner - Fundación para el Estudio del Glaucoma, Buenos Aires, ArgentinaTomasz Zarnowski - Department of Diagnostics and Microsurgery of Glaucoma, Medical University, Lublin, PolandNingli Wang - Capital Medical UniversityMohammad Pakravan - Shahid Beheshti University of Medical SciencesZhenglin Yang - University of Electronic Science and Technology of ChinaLeen Abu Safieh - King Khaled Eye Specialist Hospital, Riyadh, Saudi ArabiaPaolo Frezzotti - Department of Surgery, Section of Ophthalmology, University of Siena, Siena, ItalyLiyun Jia - Capital Medical UniversityShigeru Kinoshita - Department of Ophthalmology, Kyoto Prefectural University of Medicine, Kyoto, JapanJohn H Fingert - University of Iowa, The University of Iowa Institute for Vision ResearchMasaru Inatani - Department of Ophthalmology, Faculty of Medical Science, University of Fukui, Fukui, JapanKei Tashiro - Department of Genomic Medical Sciences, Kyoto Prefectural University of Medicine, Kyoto, JapanAndré Reis - Institute of Human Genetics, Friedrich Alexander Universität Erlangen-Nürnberg, Erlangen-Nürnberg, GermanyDeepak P Edward - King Khaled Eye Specialist HospitalLouis R Pasquale - Massachusetts Eye and Ear InfirmaryToshiaki Kubota - Department of Ophthalmology, Oita University Faculty of Medicine, Oita, JapanJaney L Wiggs - Department of Ophthalmology, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts, USAFrancesca Pasutto - Institute of Human Genetics, Friedrich Alexander Universität Erlangen-Nürnberg, Erlangen-Nürnberg, GermanyFotis Topouzis - Department of Ophthalmology, Faculty of Medicine, Aristotle University of Thessaloniki, American Hellenic Educational Progressive Association Hospital, Thessaloniki, GreeceMichael Dubina - First Pavlov State Medical University of St. PetersburgJamie E Craig - Department of Ophthalmology, Flinders University, Adelaide, South Australia, AustraliaNagahisa Yoshimura - Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Kyoto, JapanPeriasamy Sundaresan - Department of Genetics, Aravind Medical Research Foundation, Madurai, IndiaSimon W M John - Howard Hughes Medical Institute, Jackson Laboratory, Bar Harbor, Maine, USARobert Ritch - Einhorn Clinical Research Center, New York Eye and Ear Infirmary of Mount Sinai, New York, New York, USAMichael A Hauser - Duke UniversityChiea-Chuen Khor - National University of SingaporeChing Yu Cheng - National University of SingaporeXueyi Chen - First Affiliated Hospital of Xinjiang Medical UniversityYa Xing Wang
- Contributors
- Blue Mountains Eye Study GWAS Team (Institution)
- Resource Type
- Journal article
- Publication Details
- Nature genetics, Vol.47(4), pp.387-392
- DOI
- 10.1038/ng.3226
- PMID
- 25706626
- PMCID
- PMC4605818
- NLM abbreviation
- Nat Genet
- ISSN
- 1061-4036
- eISSN
- 1546-1718
- Publisher
- United States
- Grant note
- R01 EY011721 / NEI NIH HHS R01 EY018825 / NEI NIH HHS P30 EY014104 / NEI NIH HHS R01 EY020928 / NEI NIH HHS Howard Hughes Medical Institute EY11721 / NEI NIH HHS R01 EY023512 / NEI NIH HHS R29 EY011721 / NEI NIH HHS 085475/08/Z / Wellcome Trust EY023512 / NEI NIH HHS 085475/B/08/Z / Wellcome Trust EY018825 / NEI NIH HHS R01 EY013882 / NEI NIH HHS
- Language
- English
- Date published
- 04/2015
- Academic Unit
- Microbiology and Immunology; International Programs; Epidemiology; Internal Medicine; Ophthalmology and Visual Sciences
- Record Identifier
- 9983979975102771
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