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

doi:10.1038/ng.3226

. 2015 Apr;47(4):387-92.

doi: 10.1038/ng.3226. Epub 2015 Feb 23.

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

Tin Aung¹, Mineo Ozaki², Takanori Mizoguchi³, R Rand Allingham⁴, Zheng Li⁵, Aravind Haripriya⁶, Satoko Nakano⁷, Steffen Uebe⁸, Jeffrey M Harder⁹, Anita S Y Chan¹⁰, Mei Chin Lee¹¹, Kathryn P Burdon¹², Yury S Astakhov¹³, Khaled K Abu-Amero¹⁴, Juan C Zenteno¹⁵, Yildirim Nilgün¹⁶, Tomasz Zarnowski¹⁷, Mohammad Pakravan¹⁸, Leen Abu Safieh¹⁹, Liyun Jia²⁰, Ya Xing Wang²¹, Susan Williams²², Daniela Paoli²³, Patricio G Schlottmann²⁴, Lulin Huang²⁵, Kar Seng Sim⁵, Jia Nee Foo⁵, Masakazu Nakano²⁶, Yoko Ikeda²⁷, Rajesh S Kumar²⁸, Morio Ueno²⁷, Shin-ichi Manabe²⁹, Ken Hayashi²⁹, Shigeyasu Kazama³⁰, Ryuichi Ideta³¹, Yosai Mori³², Kazunori Miyata³³, Kazuhisa Sugiyama³⁴, Tomomi Higashide³⁴, Etsuo Chihara³⁵, Kenji Inoue³⁶, Satoshi Ishiko³⁷, Akitoshi Yoshida³⁸, Masahide Yanagi³⁹, Yoshiaki Kiuchi³⁹, Makoto Aihara⁴⁰, Tsutomu Ohashi⁴¹, Toshiya Sakurai⁴², Takako Sugimoto⁴³, Hideki Chuman⁴³, Fumihiko Matsuda⁴⁴, Kenji Yamashiro⁴⁵, Norimoto Gotoh⁴⁵, Masahiro Miyake⁴⁶, Sergei Y Astakhov¹³, Essam A Osman⁴⁷, Saleh A Al-Obeidan⁴⁷, Ohoud Owaidhah¹⁸, Leyla Al-Jasim¹⁸, Sami Al Shahwan¹⁸, Rhys A Fogarty⁴⁸, Paul Leo⁴⁹, Yaz Yetkin¹⁶, Çilingir Oğuz¹⁶, Mozhgan Rezaei Kanavi¹⁸, Afsaneh Nederi Beni¹⁸, Shahin Yazdani¹⁸, Evgeny L Akopov¹³, Kai-Yee Toh⁵, Gareth R Howell⁹, Andrew C Orr⁵⁰, Yufen Goh⁵, Wee Yang Meah⁵, Su Qin Peh⁵, Ewa Kosior-Jarecka¹⁷, Urszula Lukasik¹⁷, Mandy Krumbiegel⁸, Eranga N Vithana¹¹, Tien Yin Wong⁵¹, Yutao Liu⁵², Allison E Ashley Koch⁵³, Pratap Challa⁴, Robyn M Rautenbach⁵⁴, David A Mackey⁵⁵, Alex W Hewitt⁵⁶, Paul Mitchell⁵⁷, Jie Jin Wang⁵⁷, Ari Ziskind⁵⁴, Trevor Carmichael²², Rangappa Ramakrishnan⁶, Kalpana Narendran⁶, Rangaraj Venkatesh⁶, Saravanan Vijayan⁵⁸, Peiquan Zhao⁵⁹, Xueyi Chen⁶⁰, Dalia Guadarrama-Vallejo¹⁵, Ching Yu Cheng⁶¹, Shamira A Perera¹⁰, Rahat Husain¹⁰, Su-Ling Ho⁶², Ulrich-Christoph Welge-Luessen⁶³, Christian Mardin⁶³, Ursula Schloetzer-Schrehardt⁶³, Axel M Hillmer⁶⁴, Stefan Herms⁶⁵, Susanne Moebus⁶⁶, Markus M Nöthen⁶⁷, Nicole Weisschuh⁶⁸, Rohit Shetty²⁸, Arkasubhra Ghosh⁶⁹, Yik Ying Teo⁷⁰, Matthew A Brown⁴⁹, Ignacio Lischinsky⁷¹; Blue Mountains Eye Study GWAS Team; Wellcome Trust Case Control Consortium 2; Jonathan G Crowston⁷², Michael Coote⁷², Bowen Zhao¹⁹, Jinghong Sang²⁰, Nihong Zhang²⁰, Qisheng You²¹, Vera Vysochinskaya⁷³, Panayiota Founti⁷⁴, Anthoula Chatzikyriakidou⁷⁵, Alexandros Lambropoulos⁷⁵, Eleftherios Anastasopoulos⁷⁴, Anne L Coleman⁷⁶, M Roy Wilson⁷⁷, Douglas J Rhee⁷⁸, Jae Hee Kang⁷⁹, Inna May-Bolchakova⁸⁰, Steffen Heegaard⁸¹, Kazuhiko Mori²⁶, Wallace L M Alward⁸², Jost B Jonas⁸³, Liang Xu²¹, Jeffrey M Liebmann⁸⁴, Balram Chowbay⁸⁵, Elke Schaeffeler⁸⁶, Matthias Schwab⁸⁷, Fabian Lerner⁸⁸, Ningli Wang²⁰, Zhenglin Yang²⁵, Paolo Frezzotti⁸⁹, Shigeru Kinoshita²⁷, John H Fingert⁸², Masaru Inatani⁹⁰, Kei Tashiro²⁶, André Reis⁸, Deepak P Edward⁹¹, Louis R Pasquale⁹², Toshiaki Kubota⁷, Janey L Wiggs⁷⁸, Francesca Pasutto⁸, Fotis Topouzis⁷⁴, Michael Dubina⁹³, Jamie E Craig⁴⁸, Nagahisa Yoshimura⁴⁵, Periasamy Sundaresan⁵⁸, Simon W M John⁹, Robert Ritch⁹⁴, Michael A Hauser⁹⁵, Chiea-Chuen Khor⁹⁶

Collaborators, Affiliations

Collaborators

Jie Jin Wang, Paul Mitchell, Elena Rochtchina, Ananth C Viswanathan, Tien Y Wong, Jing Xie, Xueling Sim, Michael Inouye, Elizabeth G Holliday, John Attia, Rodney J Scott, Paul N Baird, Peter Donnelly, Ines Barroso, Jenefer M Blackwell, Elvira Bramon, Matthew A Brown, Juan P Casas, Aiden Corvin, Panos Deloukas, Audrey Duncanson, Janusz Jankowski, Hugh S Markus, Christopher G Mathew, Colin N A Palmer, Robert Plomin, Anna Rautanen, Stephen J Sawcer, Richard C Trembath, Ananth C Viswanathan, Nicholas W Wood, Chris C A Spencer, Gavin Band, Céline Bellenguez, Colin Freeman, Garrett Hellenthal, Eleni Giannoulatou, Matti Pirinen, Richard Pearson, Amy Strange, Zhan Su, Damjan Vukcevic, Cordelia Langford, Sarah E Hunt, Sarah Edkins, Rhian Gwilliam, Hannah Blackburn, Suzannah J Bumpstead, Serge Dronov, Matthew Gillman, Emma Gray, Naomi Hammond, Alagurevathi Jayakumar, Owen T McCann, Jennifer Liddle, Simon C Potter, Radhi Ravindrarajah, Michelle Ricketts, Matthew Waller, Paul Weston, Sara Widaa, Pamela Whittaker

Affiliations

¹ 1] Singapore Eye Research Institute, Singapore. [2] Singapore National Eye Center, Singapore. [3] Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore. [4] Division of Human Genetics, Genome Institute of Singapore, Singapore. [5] Duke University-National University of Singapore Graduate Medical School, Singapore.
² 1] Ozaki Eye Hospital, Hyuga, Japan. [2] Hayashi Eye Hospital, Fukuoka, Japan.
³ Mizoguchi Eye Hospital, Sasebo, Japan.
⁴ Department of Ophthalmology, Duke University Eye Center, Durham, North Carolina, USA.
⁵ Division of Human Genetics, Genome Institute of Singapore, Singapore.
⁶ Intraocular Lens and Cataract Clinic, Aravind Eye Hospital, Madurai, India.
⁷ Department of Ophthalmology, Oita University Faculty of Medicine, Oita, Japan.
⁸ Institute of Human Genetics, Friedrich Alexander Universität Erlangen-Nürnberg, Erlangen-Nürnberg, Germany.
⁹ Howard Hughes Medical Institute, Jackson Laboratory, Bar Harbor, Maine, USA.
¹⁰ 1] Singapore Eye Research Institute, Singapore. [2] Singapore National Eye Center, Singapore.
¹¹ Singapore Eye Research Institute, Singapore.
¹² 1] Department of Ophthalmology, Flinders University, Adelaide, South Australia, Australia. [2] Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia.
¹³ Department of Ophthalmology, First Pavlov State Medical University of St. Petersburg, St. Petersburg, Russia.
¹⁴ 1] Department of Ophthalmology, College of Medicine, King Saud University, Riyadh, Saudi Arabia. [2] Department of Ophthalmology, College of Medicine, University of Florida, Jacksonville, Florida, USA.
¹⁵ 1] Department of Genetics, Institute of Ophthalmology Conde de Valenciana, Mexico City, Mexico. [2] Department of Biochemistry, Faculty of Medicine, Universidad Nacional Autónoma de México, Mexico City, Mexico.
¹⁶ Department of Ophthalmology, Eskisehir Osmangazi University, Meselik, Turkey.
¹⁷ Department of Diagnostics and Microsurgery of Glaucoma, Medical University, Lublin, Poland.
¹⁸ Department of Ophthalmology, Ophthalmic Research Center, Labbafinejad Medical Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
¹⁹ King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia.
²⁰ Beijing Ophthalmology and Visual Sciences Key Laboratory, Beijing Tongren Eye Centre, Beijing Tongren Hospital, Capital Medical University, Beijing, China.
²¹ Beijing Institute of Ophthalmology, Beijing Tongren Hospital, Capital University of Medical Science, Beijing, China.
²² Division of Ophthalmology, Department of Neurosciences, University of the Witwatersrand, Johannesburg, South Africa.
²³ Department of Ophthalmology, Monfalcone Hospital, Gorizia, Italy.
²⁴ Organización Médica de Investigación, Buenos Aires, Argentina.
²⁵ 1] Sichuan Provincial Key Laboratory for Human Disease Gene Study, Hospital of the University of Electronic Science and Technology of China and Sichuan Provincial People's Hospital, Chengdu, China. [2] School of Medicine, University of Electronic Science and Technology of China, Chengdu, China. [3] Sichuan Translational Medicine Hospital, Chinese Academy of Sciences, Chengdu, China.
²⁶ Department of Genomic Medical Sciences, Kyoto Prefectural University of Medicine, Kyoto, Japan.
²⁷ Department of Ophthalmology, Kyoto Prefectural University of Medicine, Kyoto, Japan.
²⁸ Glaucoma Services, Narayana Nethralaya Eye Hospital, Bangalore, India.
²⁹ Hayashi Eye Hospital, Fukuoka, Japan.
³⁰ Shinjo Eye Clinic, Miyazaki, Japan.
³¹ Ideta Eye Hospital, Kumamoto, Japan.
³² Miyata Eye Hospital, Miyazaki, Japan.
³³ 1] Miyata Eye Hospital, Miyazaki, Japan. [2] Department of Ophthalmology, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan.
³⁴ Department of Ophthalmology and Visual Science, Kanazawa University Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan.
³⁵ Sensho-kai Eye Institute, Kyoto, Japan.
³⁶ Inouye Eye Hospital, Tokyo, Japan.
³⁷ Department of Medicine and Engineering Combined Research Institute, Asahikawa Medical University, Asahikawa, Japan.
³⁸ Department of Ophthalmology, Asahikawa Medical University, Asahikawa, Japan.
³⁹ Department of Ophthalmology and Visual Science, Hiroshima University, Hiroshima, Japan.
⁴⁰ Yotsuya Shirato Eye Clinic, Tokyo, Japan.
⁴¹ Ohashi Eye Center, Sapporo, Japan.
⁴² Tane Memorial Eye Hospital, Osaka, Japan.
⁴³ Department of Ophthalmology, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan.
⁴⁴ Center for Genomic Medicine/INSERM U852, Kyoto University Graduate School of Medicine, Kyoto, Japan.
⁴⁵ Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Kyoto, Japan.
⁴⁶ 1] Center for Genomic Medicine/INSERM U852, Kyoto University Graduate School of Medicine, Kyoto, Japan. [2] Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Kyoto, Japan.
⁴⁷ Department of Ophthalmology, College of Medicine, King Saud University, Riyadh, Saudi Arabia.
⁴⁸ Department of Ophthalmology, Flinders University, Adelaide, South Australia, Australia.
⁴⁹ University of Queensland Diamantina Institute, Translational Research Institute, Princess Alexandra Hospital, Brisbane, Queensland, Australia.
⁵⁰ Department of Ophthalmology and Visual Sciences, Dalhousie University, Halifax, Nova Scotia, Canada.
⁵¹ 1] Singapore Eye Research Institute, Singapore. [2] Singapore National Eye Center, Singapore. [3] Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
⁵² 1] Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA. [2] Department of Cellular Biology and Anatomy, Georgia Regents University, Augusta, Georgia, USA.
⁵³ Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA.
⁵⁴ Division of Ophthalmology, Faculty of Medicine and Health Sciences, University of Stellenbosch, Cape Town, South Africa.
⁵⁵ Centre for Ophthalmology and Visual Science, Lions Eye Institute, University of Western Australia, Perth, Western Australia, Australia.
⁵⁶ 1] Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia. [2] Centre for Eye Research Australia (CERA), University of Melbourne, Royal Victorian Eye and Ear Hospital, Melbourne, Victoria, Australia.
⁵⁷ Centre for Vision Research, Department of Ophthalmology and Westmead Millennium Institute, University of Sydney, Sydney, New South Wales, Australia.
⁵⁸ Department of Genetics, Aravind Medical Research Foundation, Madurai, India.
⁵⁹ Department of Ophthalmology, Xin Hua Hospital affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai, China.
⁶⁰ Department of Ophthalmology, First Affiliated Hospital of Xinjiang Medical University, Urumchi, Xinjiang Uygur Autonomous Region, China.
⁶¹ 1] Singapore Eye Research Institute, Singapore. [2] Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
⁶² National Healthcare Group Eye Institute, Tan Tock Seng Hospital, Singapore.
⁶³ Department of Ophthalmology, Friedrich Alexander Universität Erlangen-Nürnberg, Erlangen-Nürnberg, Germany.
⁶⁴ Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, Singapore.
⁶⁵ 1] Institute of Human Genetics, University of Bonn, Bonn, Germany. [2] Department of Genomics, Life &Brain Center, University of Bonn, Bonn, Germany. [3] Division of Medical Genetics, University Hospital, Basel, Switzerland. [4] Human Genetics Research Group, Department of Biomedicine, University of Basel, Basel, Switzerland.
⁶⁶ Institute for Medical Informatics, Biometry and Epidemiology, University Hospital of Essen, University Duisburg-Essen, Essen, Germany.
⁶⁷ 1] Institute of Human Genetics, University of Bonn, Bonn, Germany. [2] Department of Genomics, Life &Brain Center, University of Bonn, Bonn, Germany.
⁶⁸ Institute for Ophthalmic Research, Department of Ophthalmology, Tübingen, Germany.
⁶⁹ 1] Singapore Eye Research Institute, Singapore. [2] Genes, Repair and Regeneration in Ophthalmic Workstation Research Laboratory, Narayana Nethralaya Foundation, Bangalore, India.
⁷⁰ 1] Department of Ophthalmology, Duke University Eye Center, Durham, North Carolina, USA. [2] Saw Swee Hock School of Public Health, National University of Singapore, Singapore.
⁷¹ Centro Oftalmológico Lischinsky, Tucumán, Argentina.
⁷² 1] Centre for Eye Research Australia (CERA), University of Melbourne, Royal Victorian Eye and Ear Hospital, Melbourne, Victoria, Australia. [2] Department of Ophthalmology, University of Melbourne, Melbourne, Victoria, Australia.
⁷³ St. Petersburg Academic University, St. Petersburg, Russia.
⁷⁴ Department of Ophthalmology, Faculty of Medicine, Aristotle University of Thessaloniki, American Hellenic Educational Progressive Association Hospital, Thessaloniki, Greece.
⁷⁵ Department of Biology and Genetics, Faculty of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece.
⁷⁶ Center for Community Outreach and Policy, Stein Eye Institute, David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, California, USA.
⁷⁷ Wayne State University, Detroit, Michigan, USA.
⁷⁸ Department of Ophthalmology, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts, USA.
⁷⁹ Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.
⁸⁰ Department of Ophthalmology, Military Hospital Begin, Paris, France.
⁸¹ 1] Eye Pathology Institute, Department of Neuroscience and Pharmacology, University of Copenhagen, Copenhagen, Denmark. [2] Department of Ophthalmology, Glostrup University Hospital, Glostrup, Denmark.
⁸² 1] Stephen A. Wynn Institute for Vision Research, University of Iowa, Iowa City, Iowa, USA. [2] Department of Ophthalmology and Visual Sciences, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA.
⁸³ Department of Ophthalmology, Medical Faculty Mannheim of the Ruprecht Karls University Heidelberg, Heidelberg, Germany.
⁸⁴ New York University School of Medicine, Manhattan Eye, Ear and Throat Hospital, New York, New York, USA.
⁸⁵ Division of Medical Sciences, Humphrey Oei Institute of Cancer Research, National Cancer Centre of Singapore, Singapore.
⁸⁶ Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany.
⁸⁷ 1] Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany. [2] Department of Clinical Pharmacology, University Hospital, Tübingen, Germany. [3] German Cancer Consortium (DKTK), German Cancer Research Center, Heidelberg, Germany.
⁸⁸ Fundación para el Estudio del Glaucoma, Buenos Aires, Argentina.
⁸⁹ Department of Surgery, Section of Ophthalmology, University of Siena, Siena, Italy.
⁹⁰ Department of Ophthalmology, Faculty of Medical Science, University of Fukui, Fukui, Japan.
⁹¹ 1] King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia. [2] Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
⁹² 1] Department of Ophthalmology, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts, USA. [2] Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.
⁹³ 1] Department of Ophthalmology, First Pavlov State Medical University of St. Petersburg, St. Petersburg, Russia. [2] St. Petersburg Academic University, St. Petersburg, Russia.
⁹⁴ Einhorn Clinical Research Center, New York Eye and Ear Infirmary of Mount Sinai, New York, New York, USA.
⁹⁵ 1] Department of Ophthalmology, Duke University Eye Center, Durham, North Carolina, USA. [2] Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA.
⁹⁶ 1] Singapore Eye Research Institute, Singapore. [2] Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore. [3] Division of Human Genetics, Genome Institute of Singapore, Singapore.

PMID: 25706626
PMCID: PMC4605818
DOI: 10.1038/ng.3226

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

Tin Aung et al. Nat Genet. 2015 Apr.

. 2015 Apr;47(4):387-92.

doi: 10.1038/ng.3226. Epub 2015 Feb 23.

Authors

Collaborators

Jie Jin Wang, Paul Mitchell, Elena Rochtchina, Ananth C Viswanathan, Tien Y Wong, Jing Xie, Xueling Sim, Michael Inouye, Elizabeth G Holliday, John Attia, Rodney J Scott, Paul N Baird, Peter Donnelly, Ines Barroso, Jenefer M Blackwell, Elvira Bramon, Matthew A Brown, Juan P Casas, Aiden Corvin, Panos Deloukas, Audrey Duncanson, Janusz Jankowski, Hugh S Markus, Christopher G Mathew, Colin N A Palmer, Robert Plomin, Anna Rautanen, Stephen J Sawcer, Richard C Trembath, Ananth C Viswanathan, Nicholas W Wood, Chris C A Spencer, Gavin Band, Céline Bellenguez, Colin Freeman, Garrett Hellenthal, Eleni Giannoulatou, Matti Pirinen, Richard Pearson, Amy Strange, Zhan Su, Damjan Vukcevic, Cordelia Langford, Sarah E Hunt, Sarah Edkins, Rhian Gwilliam, Hannah Blackburn, Suzannah J Bumpstead, Serge Dronov, Matthew Gillman, Emma Gray, Naomi Hammond, Alagurevathi Jayakumar, Owen T McCann, Jennifer Liddle, Simon C Potter, Radhi Ravindrarajah, Michelle Ricketts, Matthew Waller, Paul Weston, Sara Widaa, Pamela Whittaker

Affiliations

¹ 1] Singapore Eye Research Institute, Singapore. [2] Singapore National Eye Center, Singapore. [3] Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore. [4] Division of Human Genetics, Genome Institute of Singapore, Singapore. [5] Duke University-National University of Singapore Graduate Medical School, Singapore.
² 1] Ozaki Eye Hospital, Hyuga, Japan. [2] Hayashi Eye Hospital, Fukuoka, Japan.
³ Mizoguchi Eye Hospital, Sasebo, Japan.
⁴ Department of Ophthalmology, Duke University Eye Center, Durham, North Carolina, USA.
⁵ Division of Human Genetics, Genome Institute of Singapore, Singapore.
⁶ Intraocular Lens and Cataract Clinic, Aravind Eye Hospital, Madurai, India.
⁷ Department of Ophthalmology, Oita University Faculty of Medicine, Oita, Japan.
⁸ Institute of Human Genetics, Friedrich Alexander Universität Erlangen-Nürnberg, Erlangen-Nürnberg, Germany.
⁹ Howard Hughes Medical Institute, Jackson Laboratory, Bar Harbor, Maine, USA.
¹⁰ 1] Singapore Eye Research Institute, Singapore. [2] Singapore National Eye Center, Singapore.
¹¹ Singapore Eye Research Institute, Singapore.
¹² 1] Department of Ophthalmology, Flinders University, Adelaide, South Australia, Australia. [2] Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia.
¹³ Department of Ophthalmology, First Pavlov State Medical University of St. Petersburg, St. Petersburg, Russia.
¹⁴ 1] Department of Ophthalmology, College of Medicine, King Saud University, Riyadh, Saudi Arabia. [2] Department of Ophthalmology, College of Medicine, University of Florida, Jacksonville, Florida, USA.
¹⁵ 1] Department of Genetics, Institute of Ophthalmology Conde de Valenciana, Mexico City, Mexico. [2] Department of Biochemistry, Faculty of Medicine, Universidad Nacional Autónoma de México, Mexico City, Mexico.
¹⁶ Department of Ophthalmology, Eskisehir Osmangazi University, Meselik, Turkey.
¹⁷ Department of Diagnostics and Microsurgery of Glaucoma, Medical University, Lublin, Poland.
¹⁸ Department of Ophthalmology, Ophthalmic Research Center, Labbafinejad Medical Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
¹⁹ King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia.
²⁰ Beijing Ophthalmology and Visual Sciences Key Laboratory, Beijing Tongren Eye Centre, Beijing Tongren Hospital, Capital Medical University, Beijing, China.
²¹ Beijing Institute of Ophthalmology, Beijing Tongren Hospital, Capital University of Medical Science, Beijing, China.
²² Division of Ophthalmology, Department of Neurosciences, University of the Witwatersrand, Johannesburg, South Africa.
²³ Department of Ophthalmology, Monfalcone Hospital, Gorizia, Italy.
²⁴ Organización Médica de Investigación, Buenos Aires, Argentina.
²⁵ 1] Sichuan Provincial Key Laboratory for Human Disease Gene Study, Hospital of the University of Electronic Science and Technology of China and Sichuan Provincial People's Hospital, Chengdu, China. [2] School of Medicine, University of Electronic Science and Technology of China, Chengdu, China. [3] Sichuan Translational Medicine Hospital, Chinese Academy of Sciences, Chengdu, China.
²⁶ Department of Genomic Medical Sciences, Kyoto Prefectural University of Medicine, Kyoto, Japan.
²⁷ Department of Ophthalmology, Kyoto Prefectural University of Medicine, Kyoto, Japan.
²⁸ Glaucoma Services, Narayana Nethralaya Eye Hospital, Bangalore, India.
²⁹ Hayashi Eye Hospital, Fukuoka, Japan.
³⁰ Shinjo Eye Clinic, Miyazaki, Japan.
³¹ Ideta Eye Hospital, Kumamoto, Japan.
³² Miyata Eye Hospital, Miyazaki, Japan.
³³ 1] Miyata Eye Hospital, Miyazaki, Japan. [2] Department of Ophthalmology, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan.
³⁴ Department of Ophthalmology and Visual Science, Kanazawa University Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan.
³⁵ Sensho-kai Eye Institute, Kyoto, Japan.
³⁶ Inouye Eye Hospital, Tokyo, Japan.
³⁷ Department of Medicine and Engineering Combined Research Institute, Asahikawa Medical University, Asahikawa, Japan.
³⁸ Department of Ophthalmology, Asahikawa Medical University, Asahikawa, Japan.
³⁹ Department of Ophthalmology and Visual Science, Hiroshima University, Hiroshima, Japan.
⁴⁰ Yotsuya Shirato Eye Clinic, Tokyo, Japan.
⁴¹ Ohashi Eye Center, Sapporo, Japan.
⁴² Tane Memorial Eye Hospital, Osaka, Japan.
⁴³ Department of Ophthalmology, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan.
⁴⁴ Center for Genomic Medicine/INSERM U852, Kyoto University Graduate School of Medicine, Kyoto, Japan.
⁴⁵ Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Kyoto, Japan.
⁴⁶ 1] Center for Genomic Medicine/INSERM U852, Kyoto University Graduate School of Medicine, Kyoto, Japan. [2] Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Kyoto, Japan.
⁴⁷ Department of Ophthalmology, College of Medicine, King Saud University, Riyadh, Saudi Arabia.
⁴⁸ Department of Ophthalmology, Flinders University, Adelaide, South Australia, Australia.
⁴⁹ University of Queensland Diamantina Institute, Translational Research Institute, Princess Alexandra Hospital, Brisbane, Queensland, Australia.
⁵⁰ Department of Ophthalmology and Visual Sciences, Dalhousie University, Halifax, Nova Scotia, Canada.
⁵¹ 1] Singapore Eye Research Institute, Singapore. [2] Singapore National Eye Center, Singapore. [3] Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
⁵² 1] Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA. [2] Department of Cellular Biology and Anatomy, Georgia Regents University, Augusta, Georgia, USA.
⁵³ Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA.
⁵⁴ Division of Ophthalmology, Faculty of Medicine and Health Sciences, University of Stellenbosch, Cape Town, South Africa.
⁵⁵ Centre for Ophthalmology and Visual Science, Lions Eye Institute, University of Western Australia, Perth, Western Australia, Australia.
⁵⁶ 1] Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia. [2] Centre for Eye Research Australia (CERA), University of Melbourne, Royal Victorian Eye and Ear Hospital, Melbourne, Victoria, Australia.
⁵⁷ Centre for Vision Research, Department of Ophthalmology and Westmead Millennium Institute, University of Sydney, Sydney, New South Wales, Australia.
⁵⁸ Department of Genetics, Aravind Medical Research Foundation, Madurai, India.
⁵⁹ Department of Ophthalmology, Xin Hua Hospital affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai, China.
⁶⁰ Department of Ophthalmology, First Affiliated Hospital of Xinjiang Medical University, Urumchi, Xinjiang Uygur Autonomous Region, China.
⁶¹ 1] Singapore Eye Research Institute, Singapore. [2] Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
⁶² National Healthcare Group Eye Institute, Tan Tock Seng Hospital, Singapore.
⁶³ Department of Ophthalmology, Friedrich Alexander Universität Erlangen-Nürnberg, Erlangen-Nürnberg, Germany.
⁶⁴ Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, Singapore.
⁶⁵ 1] Institute of Human Genetics, University of Bonn, Bonn, Germany. [2] Department of Genomics, Life &Brain Center, University of Bonn, Bonn, Germany. [3] Division of Medical Genetics, University Hospital, Basel, Switzerland. [4] Human Genetics Research Group, Department of Biomedicine, University of Basel, Basel, Switzerland.
⁶⁶ Institute for Medical Informatics, Biometry and Epidemiology, University Hospital of Essen, University Duisburg-Essen, Essen, Germany.
⁶⁷ 1] Institute of Human Genetics, University of Bonn, Bonn, Germany. [2] Department of Genomics, Life &Brain Center, University of Bonn, Bonn, Germany.
⁶⁸ Institute for Ophthalmic Research, Department of Ophthalmology, Tübingen, Germany.
⁶⁹ 1] Singapore Eye Research Institute, Singapore. [2] Genes, Repair and Regeneration in Ophthalmic Workstation Research Laboratory, Narayana Nethralaya Foundation, Bangalore, India.
⁷⁰ 1] Department of Ophthalmology, Duke University Eye Center, Durham, North Carolina, USA. [2] Saw Swee Hock School of Public Health, National University of Singapore, Singapore.
⁷¹ Centro Oftalmológico Lischinsky, Tucumán, Argentina.
⁷² 1] Centre for Eye Research Australia (CERA), University of Melbourne, Royal Victorian Eye and Ear Hospital, Melbourne, Victoria, Australia. [2] Department of Ophthalmology, University of Melbourne, Melbourne, Victoria, Australia.
⁷³ St. Petersburg Academic University, St. Petersburg, Russia.
⁷⁴ Department of Ophthalmology, Faculty of Medicine, Aristotle University of Thessaloniki, American Hellenic Educational Progressive Association Hospital, Thessaloniki, Greece.
⁷⁵ Department of Biology and Genetics, Faculty of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece.
⁷⁶ Center for Community Outreach and Policy, Stein Eye Institute, David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, California, USA.
⁷⁷ Wayne State University, Detroit, Michigan, USA.
⁷⁸ Department of Ophthalmology, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts, USA.
⁷⁹ Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.
⁸⁰ Department of Ophthalmology, Military Hospital Begin, Paris, France.
⁸¹ 1] Eye Pathology Institute, Department of Neuroscience and Pharmacology, University of Copenhagen, Copenhagen, Denmark. [2] Department of Ophthalmology, Glostrup University Hospital, Glostrup, Denmark.
⁸² 1] Stephen A. Wynn Institute for Vision Research, University of Iowa, Iowa City, Iowa, USA. [2] Department of Ophthalmology and Visual Sciences, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA.
⁸³ Department of Ophthalmology, Medical Faculty Mannheim of the Ruprecht Karls University Heidelberg, Heidelberg, Germany.
⁸⁴ New York University School of Medicine, Manhattan Eye, Ear and Throat Hospital, New York, New York, USA.
⁸⁵ Division of Medical Sciences, Humphrey Oei Institute of Cancer Research, National Cancer Centre of Singapore, Singapore.
⁸⁶ Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany.
⁸⁷ 1] Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany. [2] Department of Clinical Pharmacology, University Hospital, Tübingen, Germany. [3] German Cancer Consortium (DKTK), German Cancer Research Center, Heidelberg, Germany.
⁸⁸ Fundación para el Estudio del Glaucoma, Buenos Aires, Argentina.
⁸⁹ Department of Surgery, Section of Ophthalmology, University of Siena, Siena, Italy.
⁹⁰ Department of Ophthalmology, Faculty of Medical Science, University of Fukui, Fukui, Japan.
⁹¹ 1] King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia. [2] Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
⁹² 1] Department of Ophthalmology, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts, USA. [2] Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.
⁹³ 1] Department of Ophthalmology, First Pavlov State Medical University of St. Petersburg, St. Petersburg, Russia. [2] St. Petersburg Academic University, St. Petersburg, Russia.
⁹⁴ Einhorn Clinical Research Center, New York Eye and Ear Infirmary of Mount Sinai, New York, New York, USA.
⁹⁵ 1] Department of Ophthalmology, Duke University Eye Center, Durham, North Carolina, USA. [2] Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA.
⁹⁶ 1] Singapore Eye Research Institute, Singapore. [2] Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore. [3] Division of Human Genetics, Genome Institute of Singapore, Singapore.

PMID: 25706626
PMCID: PMC4605818
DOI: 10.1038/ng.3226

Erratum in

Corrigendum: a common variant mapping to CACNA1A is associated with susceptibility to exfoliation syndrome.
Aung T, Ozaki M, Mizoguchi T, Allingham RR, Li Z, Haripriya A, Nakano S, Uebe S, Harder JM, Chan AS, Lee MC, Burdon KP, Astakhov YS, Abu-Amero KK, Zenteno JC, Nilgün Y, Zarnowski T, Pakravan M, Safieh LA, Jia L, Wang YX, Williams S, Paoli D, Schlottmann PG, Huang L, Sim KS, Foo JN, Nakano M, Ikeda Y, Kumar RS, Ueno M, Manabe S, Hayashi K, Kazama S, Ideta R, Mori Y, Miyata K, Sugiyama K, Higashide T, Chihara E, Inoue K, Ishiko S, Yoshida A, Yanagi M, Kiuchi Y, Aihara M, Ohashi T, Sakurai T, Sugimoto T, Chuman H, Matsuda F, Yamashiro K, Gotoh N, Miyake M, Astakhov SY, Osman EA, Al-Obeidan SA, Owaidhah O, Al-Jasim L, Shahwan SA, Fogarty RA, Leo P, Yetkin Y, Oğuz Ç, Kanavi MR, Beni AN, Yazdani S, Akopov EL, Toh KY, Howell GR, Orr AC, Goh Y, Meah WY, Peh SQ, Kosior-Jarecka E, Lukasik U, Krumbiegel M, Vithana EN, Wong TY, Liu Y, Koch AE, Challa P, Rautenbach RM, Mackey DA, Hewitt AW, Mitchell P, Wang JJ, Ziskind A, Carmichael T, Ramakrishnan R, Narendran K, Venkatesh R, Vijayan S, Zhao P, Chen X, Guadarrama-Vallejo D, Cheng CY, Perera SA, Husain R, Ho SL, Welge-Luessen UC, Mardin C, Schloetzer-Schrehardt U, Hillmer AM, Herms S, Moebus S, Nöthen MM, Weisschuh N, Shetty R, Ghosh A, Teo YY… See abstract for full author list ➔ Aung T, et al. Nat Genet. 2015 Jun;47(6):689. doi: 10.1038/ng0615-689c. Nat Genet. 2015. PMID: 26018902 No abstract available.

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.

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Conflict of interest statement

COMPETING FINANCIAL INTERESTS

The authors declare no competing financial interests.

Figures

**Figure 1**
Forest plot for the associations between *CACNA1A* rs4926244 and Exfoliation syndrome in discovery and follow up case-control collections. The black lines denote the 95% confidence intervals of the odds ratio for each collection. The diamonds denote summary results for the GWAS, Validation and Replication stages (blue), as well as the GWAS and Validation meta-analysis, and meta-analysis of data from all collections (red). Asian and European ethnic summaries are in black diamonds.

**Figure 2**
Regional association and recombination rate plot for the *CACNA1A* rs4926244 locus. The left y axis represents –log10 P values for association with exfoliation syndrome and the right y axis represents the recombination rate. The x axis represents base-pair positions along the chromosome (human genome Build 37). The diamonds denote the summary of each experimental stage, a) for the GWAS discovery, b) for the meta-analysis between GWAS discovery and validation stages, and c) for the meta-analysis between GWAS discovery, validation, and replication stages.

**Figure 3**
CACNA1A and LOXL1 protein expression and light microscopic analysis in XFS and non-XFS control eyes. Immunolocalisation of CACNA1A in human non-XFS and XFS globes show CACNA1A positive immunoreactivity in the smooth musculature of the ciliary body (CB) and pigmented and non-pigmented ciliary process (CP) epithelium with variable staining in the zonules (Panels a to c: CACNA1A immunofluorescence (IF) panel; CACNA1A immunohistochemical (IHC) panel, 40x; zonules, white and black arrows; exfoliated material, green asterix). In contrast, LOXL1 immunoreactivity is present only in the exfoliated material and the CP epithelium, (LOXL1 IF panel; zonules, white arrows). Double immunofluorecence analysis shows colocalisation of CACNA1A and LOXL1 within the non-pigmented and pigmented epithelium of the CP but not in the CB smooth muscles or the zonules (IF overlay panel; zonules, white arrows). Light microscopy comparison of non-XFS and XFS irides show the typical XFS findings of exfoliated material (green asterix) on the posterior iris and atrophic iris pigment epithelium with possible atrophy of the iris dilator muscle (blue arrowheads) in XFS irides. The sphincter pupillae in both non-XFS and XFS shows negligible differences (H&E panels). CACNA1A positive immunoreactivity is also seen in the anterior iris border, iris stromal cells, the iris dilator (blue arrowheads, H&E and IHC panels) and sphincter muscles as well as the iris pigmented epithelium in both XFS and Non-XFS irides (Panel d & e: CACNA1A IF and CACNA1A IHC panels). Stromal cells are highlighted by the blue circles. For CACNA1A, LOXL1, and overlay panels a) through to d), each unit on the scale bar represents 100 μm. For CACNA1A IHC panels a) to d), each unit on the scale bar represents 50 μm. For panel e) hematoxylin & eosin non-XFS as well as hematoxylin & eosin XFS1, each unit on the scale bar represents 200 μm. For panel e) CACNA1A IHC XFS2 as well as CACNA1A IHC non-XFS, each unit on the scale bar represents 25 μm.

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References

1. Schlotzer-Schrehardt U, Naumann GO. Ocular and systemic pseudoexfoliation syndrome. Am J Ophthalmol. 2006;141:921–937. - PubMed
1. Ritch R, Schlotzer-Schrehardt U. Exfoliation syndrome. Surv Ophthalmol. 2001;45:265–315. - PubMed
1. Thorleifsson G, et al. Common sequence variants in the LOXL1 gene confer susceptibility to exfoliation glaucoma. Science. 2007;317:1397–400. - PubMed
1. Chen H, et al. Ethnicity-based subgroup meta-analysis of the association of LOXL1 polymorphisms with glaucoma. Mol Vis. 2010;16:167–77. - PMC - PubMed
1. Fingert JH, et al. LOXL1 mutations are associated with exfoliation syndrome in patients from the midwestern United States. Am J Ophthalmol. 2007;144:974–975. - PubMed

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[1] Schlotzer-Schrehardt U, Naumann GO. Ocular and systemic pseudoexfoliation syndrome. Am J Ophthalmol. 2006;141:921–937. - PubMed

[2] Schlotzer-Schrehardt U, Naumann GO. Ocular and systemic pseudoexfoliation syndrome. Am J Ophthalmol. 2006;141:921–937. - PubMed

[3] Ritch R, Schlotzer-Schrehardt U. Exfoliation syndrome. Surv Ophthalmol. 2001;45:265–315. - PubMed

[4] Ritch R, Schlotzer-Schrehardt U. Exfoliation syndrome. Surv Ophthalmol. 2001;45:265–315. - PubMed

[5] Thorleifsson G, et al. Common sequence variants in the LOXL1 gene confer susceptibility to exfoliation glaucoma. Science. 2007;317:1397–400. - PubMed

[6] Thorleifsson G, et al. Common sequence variants in the LOXL1 gene confer susceptibility to exfoliation glaucoma. Science. 2007;317:1397–400. - PubMed

[7] Chen H, et al. Ethnicity-based subgroup meta-analysis of the association of LOXL1 polymorphisms with glaucoma. Mol Vis. 2010;16:167–77. - PMC - PubMed

[8] Chen H, et al. Ethnicity-based subgroup meta-analysis of the association of LOXL1 polymorphisms with glaucoma. Mol Vis. 2010;16:167–77. - PMC - PubMed

[9] Fingert JH, et al. LOXL1 mutations are associated with exfoliation syndrome in patients from the midwestern United States. Am J Ophthalmol. 2007;144:974–975. - PubMed

[10] Fingert JH, et al. LOXL1 mutations are associated with exfoliation syndrome in patients from the midwestern United States. Am J Ophthalmol. 2007;144:974–975. - PubMed

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

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