A common variant mapping to CACNA1A is associated with susceptibility to exfoliation syndrome

Tin Aung; Mineo Ozaki; Takanori Mizoguchi; R Rand Allingham; Zheng Li; Aravind Haripriya; Satoko Nakano; Steffen Uebe; Jeffrey M Harder; Anita S Y Chan; Mei Chin Lee; Kathryn P Burdon; Yury S Astakhov; Khaled K Abu-Amero; Juan C Zenteno; Yildirim Nilgün; Tomasz Zarnowski; Mohammad Pakravan; Leen Abu Safieh; Liyun Jia; Ya Xing Wang; Susan Williams; Daniela Paoli; Patricio G Schlottmann; Lulin Huang; Kar Seng Sim; Jia Nee Foo; Masakazu Nakano; Yoko Ikeda; Rajesh S Kumar; Morio Ueno; Shin-ichi Manabe; Ken Hayashi; Shigeyasu Kazama; Ryuichi Ideta; Yosai Mori; Kazunori Miyata; Kazuhisa Sugiyama; Tomomi Higashide; Etsuo Chihara; Kenji Inoue; Satoshi Ishiko; Akitoshi Yoshida; Masahide Yanagi; Yoshiaki Kiuchi; Makoto Aihara; Tsutomu Ohashi; Toshiya Sakurai; Takako Sugimoto; Hideki Chuman; Fumihiko Matsuda; Kenji Yamashiro; Norimoto Gotoh; Masahiro Miyake; Sergei Y Astakhov; Essam A Osman; Saleh A Al-Obeidan; Ohoud Owaidhah; Leyla Al-Jasim; Sami Al Shahwan; Rhys A Fogarty; Paul Leo; Yaz Yetkin; Çilingir Oğuz; Mozhgan Rezaei Kanavi; Afsaneh Nederi Beni; Shahin Yazdani; Evgeny L Akopov; Kai-Yee Toh; Gareth R Howell; Andrew C Orr; Yufen Goh; Wee Yang Meah; Su Qin Peh; Ewa Kosior-Jarecka; Urszula Lukasik; Mandy Krumbiegel; Eranga N Vithana; Tien Yin Wong; Yutao Liu; Allison E Ashley Koch; Pratap Challa; Robyn M Rautenbach; David A Mackey; Alex W Hewitt; Paul Mitchell; Jie Jin Wang; Ari Ziskind; Trevor Carmichael; Rangappa Ramakrishnan; Kalpana Narendran; Rangaraj Venkatesh; Saravanan Vijayan; Peiquan Zhao; Xueyi Chen; Dalia Guadarrama-Vallejo; Ching Yu Cheng; Shamira A Perera; Rahat Husain; Su-Ling Ho; Ulrich-Christoph Welge-Luessen; Christian Mardin; Ursula Schloetzer-Schrehardt; Axel M Hillmer; Stefan Herms; Susanne Moebus; Markus M Nöthen; Nicole Weisschuh; Rohit Shetty; Arkasubhra Ghosh; Yik Ying Teo; Matthew A Brown; Ignacio Lischinsky; Jonathan G Crowston; Michael Coote; Bowen Zhao; Jinghong Sang; Nihong Zhang; Qisheng You; Vera Vysochinskaya; Panayiota Founti; Anthoula Chatzikyriakidou; Alexandros Lambropoulos; Eleftherios Anastasopoulos; Anne L Coleman; M Roy Wilson; Douglas J Rhee; Jae Hee Kang; Inna May-Bolchakova; Steffen Heegaard; Kazuhiko Mori; Wallace L M Alward; Jost B Jonas; Liang Xu; Jeffrey M Liebmann; Balram Chowbay; Elke Schaeffeler; Matthias Schwab; Fabian Lerner; Ningli Wang; Zhenglin Yang; Paolo Frezzotti; Shigeru Kinoshita; John H Fingert; Masaru Inatani; Kei Tashiro; André Reis; Deepak P Edward; Louis R Pasquale; Toshiaki Kubota; Janey L Wiggs; Francesca Pasutto; Fotis Topouzis; Michael Dubina; Jamie E Craig; Nagahisa Yoshimura; Periasamy Sundaresan; Simon W M John; Robert Ritch; Michael A Hauser; Chiea-Chuen Khor; Blue Mountains Eye Study GWAS Team; Panos Deloukas

doi:10.1038/ng.3226

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A common variant mapping to CACNA1A is associated with susceptibility to exfoliation syndrome

Journal article

Peer reviewed

A common variant mapping to CACNA1A is associated with susceptibility to exfoliation syndrome

Tin Aung, Mineo Ozaki, Takanori Mizoguchi, R Rand Allingham, Zheng Li, Aravind Haripriya, Satoko Nakano, Steffen Uebe, Jeffrey M Harder, Anita S Y Chan, …

Nature genetics, Vol.47(4), pp.387-392

01/04/2015

DOI: https://doi.org/10.1038/ng.3226

PMCID: PMC4605818

PMID: 25706626

Abstract

Animals

Asian People - genetics

Asian People - statistics & numerical data

Calcium Channels - genetics

Case-Control Studies

Chromosome Mapping

Exfoliation Syndrome - epidemiology

Exfoliation Syndrome - genetics

Genetic Predisposition to Disease

Genome-Wide Association Study

Glaucoma, Open-Angle - epidemiology

Glaucoma, Open-Angle - genetics

HEK293 Cells

HeLa Cells

Humans

Japan - epidemiology

MCF-7 Cells

Mice

Mice, Inbred C57BL

Polymorphism, Single Nucleotide

Tumor Cells, Cultured

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.

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Title: A common variant mapping to CACNA1A is associated with susceptibility to exfoliation syndrome
Creators - without role: Tin Aung - Singapore Eye Research Institute
Mineo Ozaki - Miyata Eye Hospital
Takanori Mizoguchi - Mizoguchi Eye Hospital, Sasebo, Japan
R Rand Allingham - Duke University
Zheng Li - Genome Institute of Singapore
Aravind Haripriya - Aravind Eye Hospital
Satoko Nakano - Oita University
Steffen Uebe - Friedrich-Alexander-Universität Erlangen-Nürnberg
Jeffrey M Harder - Howard Hughes Medical Institute
Anita S Y Chan - Singapore Eye Research Institute
Mei Chin Lee - Singapore Eye Research Institute
Kathryn P Burdon - University of Tasmania
Yury S Astakhov - First Pavlov State Medical University of St. Petersburg
Khaled K Abu-Amero - King Saud University
Juan C Zenteno - Institute of Ophthalmology
Yildirim Nilgün - Eskişehir Osmangazi University
Tomasz Zarnowski - Medical University of Lublin
Mohammad Pakravan - Shahid Beheshti University of Medical Sciences
Leen Abu Safieh - King Khaled Eye Specialist Hospital
Liyun Jia - Beijing Tongren Hospital
Ya Xing Wang - Beijing Tongren Hospital
Susan Williams - University of the Witwatersrand
Daniela Paoli - Ospedale di Monfalcone
Patricio G Schlottmann - Organización Médica de Investigación, Buenos Aires, Argentina
Lulin Huang - University of Electronic Science and Technology of China
Kar Seng Sim - Genome Institute of Singapore
Jia Nee Foo - Genome Institute of Singapore
Masakazu Nakano - Kyoto Prefectural University of Medicine
Yoko Ikeda - Kyoto Prefectural University of Medicine
Rajesh S Kumar - Narayana Nethralaya
Morio Ueno - Kyoto Prefectural University of Medicine
Shin-ichi Manabe - Hayashi Eye Hospital
Ken Hayashi - Hayashi Eye Hospital
Shigeyasu Kazama - Miyata Eye Hospital
Ryuichi Ideta - Ideta Eye Hospital
Yosai Mori - Miyata Eye Hospital
Kazunori Miyata - Miyata Eye Hospital
Kazuhisa Sugiyama - Kanazawa University
Tomomi Higashide - Kanazawa University
Etsuo Chihara - Sensho-kai Eye Institute, Kyoto, Japan
Kenji Inoue - Inouye Eye Hospital
Satoshi Ishiko - Asahikawa Medical University
Akitoshi Yoshida - Asahikawa Medical University
Masahide Yanagi - Hiroshima University
Yoshiaki Kiuchi - Hiroshima University
Makoto Aihara - Yotsuya Shirato Eye Clinic, Tokyo, Japan
Tsutomu Ohashi - Ohtsuka Eye Hospital
Toshiya Sakurai - Tane General Hospital
Takako Sugimoto - University of Miyazaki
Hideki Chuman - University of Miyazaki
Fumihiko Matsuda - Kyoto University
Kenji Yamashiro - Kyoto University
Norimoto Gotoh - Kyoto University
Masahiro Miyake - Kyoto University
Sergei Y Astakhov - First Pavlov State Medical University of St. Petersburg
Essam A Osman - King Saud University
Saleh A Al-Obeidan - King Saud University
Ohoud Owaidhah - Shahid Beheshti University of Medical Sciences
Leyla Al-Jasim - Shahid Beheshti University of Medical Sciences
Sami Al Shahwan - Shahid Beheshti University of Medical Sciences
Rhys A Fogarty - Flinders University
Paul Leo - Princess Alexandra Hospital
Yaz Yetkin - Eskişehir Osmangazi University
Çilingir Oğuz - Eskişehir Osmangazi University
Mozhgan Rezaei Kanavi - Shahid Beheshti University of Medical Sciences
Afsaneh Nederi Beni - Shahid Beheshti University of Medical Sciences
Shahin Yazdani - Shahid Beheshti University of Medical Sciences
Evgeny L Akopov - First Pavlov State Medical University of St. Petersburg
Kai-Yee Toh - Genome Institute of Singapore
Gareth R Howell - Howard Hughes Medical Institute
Andrew C Orr - Dalhousie University
Yufen Goh - Genome Institute of Singapore
Wee Yang Meah - Genome Institute of Singapore
Su Qin Peh - Genome Institute of Singapore
Ewa Kosior-Jarecka - Medical University of Lublin
Urszula Lukasik - Medical University of Lublin
Mandy Krumbiegel - Friedrich-Alexander-Universität Erlangen-Nürnberg
Eranga N Vithana - Singapore Eye Research Institute
Tien Yin Wong - Singapore Eye Research Institute
Yutao Liu - Duke Medical Center
Allison E Ashley Koch - Duke Medical Center
Pratap Challa - Duke University
Robyn M Rautenbach - Western Cape Department of Health
David A Mackey - University of Western Australia
Alex W Hewitt - University of Tasmania
Paul Mitchell - University of Sydney
Jie Jin Wang - Westmead Institute
Ari Ziskind - Western Cape Department of Health
Trevor Carmichael - University of the Witwatersrand
Rangappa Ramakrishnan - Aravind Eye Hospital
Kalpana Narendran - Aravind Eye Hospital
Rangaraj Venkatesh - Aravind Eye Hospital
Saravanan Vijayan - Department of Genetics, Aravind Medical Research Foundation, Madurai, India
Peiquan Zhao - XinHua Hospital
Xueyi Chen - First Affiliated Hospital of Xinjiang Medical University
Dalia Guadarrama-Vallejo - Institute of Ophthalmology
Ching Yu Cheng - Singapore Eye Research Institute
Shamira A Perera - Singapore Eye Research Institute
Rahat Husain - Singapore Eye Research Institute
Su-Ling Ho - Tan Tock Seng Hospital
Ulrich-Christoph Welge-Luessen - Department of Ophthalmology, Friedrich Alexander Universität Erlangen-Nürnberg, Erlangen-Nürnberg, Germany
Christian Mardin - Department of Ophthalmology, Friedrich Alexander Universität Erlangen-Nürnberg, Erlangen-Nürnberg, Germany
Ursula Schloetzer-Schrehardt - Department of Ophthalmology, Friedrich Alexander Universität Erlangen-Nürnberg, Erlangen-Nürnberg, Germany
Axel M Hillmer - Genome Institute of Singapore
Stefan Herms - University Hospital of Basel
Susanne Moebus - University of Duisburg-Essen
Markus M Nöthen - University of Bonn
Nicole Weisschuh - Institute for Ophthalmic Research, Department of Ophthalmology, Tübingen, Germany
Rohit Shetty - Narayana Nethralaya
Arkasubhra Ghosh - Narayana Nethralaya
Yik Ying Teo - Duke-NUS Medical School
Matthew A Brown - University of Queensland
Ignacio Lischinsky - Centro Oftalmológico Lischinsky, Tucumán, Argentina
Jonathan G Crowston - University of Melbourne
Michael Coote - University of Melbourne
Bowen Zhao - King Khaled Eye Specialist Hospital
Jinghong Sang - Capital Medical University
Nihong Zhang - Capital Medical University
Qisheng You - Capital University
Vera Vysochinskaya - St. Petersburg Academic University, St. Petersburg, Russia
Panayiota Founti - Aristotle University of Thessaloniki
Anthoula Chatzikyriakidou - Aristotle University of Thessaloniki
Alexandros Lambropoulos - Aristotle University of Thessaloniki
Eleftherios Anastasopoulos - Aristotle University of Thessaloniki
Anne L Coleman - University of California, Los Angeles
M Roy Wilson - Wayne State University
Douglas J Rhee - Massachusetts Eye and Ear Infirmary
Jae Hee Kang - Brigham and Women's Hospital
Inna May-Bolchakova - Military Hospital
Steffen Heegaard - University of Copenhagen
Kazuhiko Mori - Kyoto Prefectural University of Medicine
Wallace L M Alward - University of Iowa
Jost B Jonas - Heidelberg
Liang Xu - Capital University
Jeffrey M Liebmann - New York University School of Medicine, Manhattan Eye, Ear and Throat Hospital, New York, New York, USA
Balram Chowbay - National Cancer Centre Singapore
Elke Schaeffeler - Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology
Matthias Schwab - 1] Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany. Department of Clinical Pharmacology, University Hospital, Tübingen, Germany. German Cancer Consortium (DKTK), German Cancer Research Center, Heidelberg, Germany
Fabian Lerner - Fundación para el Estudio del Glaucoma, Buenos Aires, Argentina
Ningli Wang - Capital Medical University
Zhenglin Yang - University of Electronic Science and Technology of China
Paolo Frezzotti - University of Siena
Shigeru Kinoshita - Kyoto Prefectural University of Medicine
John H Fingert - University of Iowa
Masaru Inatani - University of Fukui
Kei Tashiro - Kyoto Prefectural University of Medicine
André Reis - Institute of Human Genetics
Deepak P Edward - Johns Hopkins University School of Medicine
Louis R Pasquale - Massachusetts Eye and Ear Infirmary
Toshiaki Kubota - Oita University
Janey L Wiggs - Massachusetts Eye and Ear Infirmary
Francesca Pasutto - Institute of Human Genetics, Friedrich Alexander Universität Erlangen-Nürnberg, Erlangen-Nürnberg, Germany
Fotis Topouzis - Aristotle University of Thessaloniki
Michael Dubina - First Pavlov State Medical University of St. Petersburg
Jamie E Craig - Flinders University
Nagahisa Yoshimura - Kyoto University
Periasamy Sundaresan - Department of Genetics, Aravind Medical Research Foundation, Madurai, India
Simon W M John - Howard Hughes Medical Institute
Robert Ritch - New York Eye and Ear Infirmary
Michael A Hauser - Duke Medical Center
Chiea-Chuen Khor - 1] Singapore Eye Research Institute, Singapore. Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore. Division of Human Genetics, Genome Institute of Singapore, Singapore
Blue Mountains Eye Study GWAS Team
Panos Deloukas - King Abdulaziz University
Publication Details: Nature genetics, Vol.47(4), pp.387-392
Grant note: R01 EY011721 / NEI NIH HHS Wellcome Trust 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
Identifiers: 9936243108331
Academic Unit: King Abdulaziz University; King Saud University
Language: English
Resource Type: Journal article