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Nat Genet. 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.

Aung T1, Ozaki M2, Mizoguchi T3, Allingham RR4, Li Z5, Haripriya A6, Nakano S7, Uebe S8, Harder JM9, Chan AS10, Lee MC11, Burdon KP12, Astakhov YS13, Abu-Amero KK14, Zenteno JC15, Nilgün Y16, Zarnowski T17, Pakravan M18, Safieh LA19, Jia L20, Wang YX21, Williams S22, Paoli D23, Schlottmann PG24, Huang L25, Sim KS5, Foo JN5, Nakano M26, Ikeda Y27, Kumar RS28, Ueno M27, Manabe S29, Hayashi K29, Kazama S30, Ideta R31, Mori Y32, Miyata K33, Sugiyama K34, Higashide T34, Chihara E35, Inoue K36, Ishiko S37, Yoshida A38, Yanagi M39, Kiuchi Y39, Aihara M40, Ohashi T41, Sakurai T42, Sugimoto T43, Chuman H43, Matsuda F44, Yamashiro K45, Gotoh N45, Miyake M46, Astakhov SY13, Osman EA47, Al-Obeidan SA47, Owaidhah O18, Al-Jasim L18, Al Shahwan S18, Fogarty RA48, Leo P49, Yetkin Y16, Oğuz Ç16, Kanavi MR18, Beni AN18, Yazdani S18, Akopov EL13, Toh KY5, Howell GR9, Orr AC50, Goh Y5, Meah WY5, Peh SQ5, Kosior-Jarecka E17, Lukasik U17, Krumbiegel M8, Vithana EN11, Wong TY51, Liu Y52, Koch AE53, Challa P4, Rautenbach RM54, Mackey DA55, Hewitt AW56, Mitchell P57, Wang JJ57, Ziskind A54, Carmichael T22, Ramakrishnan R6, Narendran K6, Venkatesh R6, Vijayan S58, Zhao P59, Chen X60, Guadarrama-Vallejo D15, Cheng CY61, Perera SA10, Husain R10, Ho SL62, Welge-Luessen UC63, Mardin C63, Schloetzer-Schrehardt U63, Hillmer AM64, Herms S65, Moebus S66, Nöthen MM67, Weisschuh N68, Shetty R28, Ghosh A69, Teo YY70, Brown MA49, Lischinsky I71; Blue Mountains Eye Study GWAS Team; Wellcome Trust Case Control Consortium 2, Crowston JG72, Coote M72, Zhao B19, Sang J20, Zhang N20, You Q21, Vysochinskaya V73, Founti P74, Chatzikyriakidou A75, Lambropoulos A75, Anastasopoulos E74, Coleman AL76, Wilson MR77, Rhee DJ78, Kang JH79, May-Bolchakova I80, Heegaard S81, Mori K26, Alward WL82, Jonas JB83, Xu L21, Liebmann JM84, Chowbay B85, Schaeffeler E86, Schwab M87, Lerner F88, Wang N20, Yang Z25, Frezzotti P89, Kinoshita S27, Fingert JH82, Inatani M90, Tashiro K26, Reis A8, Edward DP91, Pasquale LR92, Kubota T7, Wiggs JL78, Pasutto F8, Topouzis F74, Dubina M93, Craig JE48, Yoshimura N45, Sundaresan P58, John SW9, Ritch R94, Hauser MA95, Khor CC96.

Author information

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.

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.

PMID:
25706626
PMCID:
PMC4605818
DOI:
10.1038/ng.3226
[Indexed for MEDLINE]
Free PMC Article

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