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 Ouz; 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

doi:10.1038/ng.3226

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 JiaYa 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 Ouz, 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

Research output: Contribution to journal › Article › peer-review

88 Scopus citations

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 â '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.

Original language	English (US)
Pages (from-to)	387-392
Number of pages	6
Journal	Nature Genetics
Volume	47
Issue number	4
DOIs	https://doi.org/10.1038/ng.3226
State	Published - Apr 28 2015
Externally published	Yes

ASJC Scopus subject areas

Genetics

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10.1038/ng.3226

Cite this

Aung, T., Ozaki, M., Mizoguchi, T., Allingham, R. R., Li, Z., Haripriya, A., Nakano, S., Uebe, S., Harder, J. M., Chan, A. S. Y., Lee, M. C., Burdon, K. P., Astakhov, Y. S., Abu-Amero, K. K., Zenteno, J. C., Nilgün, Y., Zarnowski, T., Pakravan, M., Safieh, L. A., ... Khor, C. C. (2015). A common variant mapping to CACNA1A is associated with susceptibility to exfoliation syndrome. Nature Genetics, 47(4), 387-392. https://doi.org/10.1038/ng.3226

Aung, T, Ozaki, M, Mizoguchi, T, Allingham, RR, Li, Z, Haripriya, A, Nakano, S, Uebe, S, Harder, JM, Chan, ASY, 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, SI, 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, Ouz, 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, AEA, 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, Brown, MA, Lischinsky, I, Crowston, JG, Coote, M, Zhao, B, Sang, J, Zhang, N, You, Q, Vysochinskaya, V, Founti, P, Chatzikyriakidou, A, Lambropoulos, A, Anastasopoulos, E, Coleman, AL, Wilson, MR, Rhee, DJ, Kang, JH, May-Bolchakova, I, Heegaard, S, Mori, K, Alward, WLM, Jonas, JB, Xu, L, Liebmann, JM, Chowbay, B, Schaeffeler, E, Schwab, M, Lerner, F, Wang, N, Yang, Z, Frezzotti, P, Kinoshita, S, Fingert, JH, Inatani, M, Tashiro, K, Reis, A, Edward, DP, Pasquale, LR, Kubota, T, Wiggs, JL, Pasutto, F, Topouzis, F, Dubina, M, Craig, JE, Yoshimura, N, Sundaresan, P, John, SWM, Ritch, R, Hauser, MA & Khor, CC 2015, 'A common variant mapping to CACNA1A is associated with susceptibility to exfoliation syndrome', Nature Genetics, vol. 47, no. 4, pp. 387-392. https://doi.org/10.1038/ng.3226

@article{1ffff059f0c54eacb25fc795ba849676,

title = "A common variant mapping to CACNA1A is associated with susceptibility to exfoliation syndrome",

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 {\^a} '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.",

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

note = "Funding Information: The authors thank the staff and participants of all studies for their important contributions. We thank K.-K. Heng, X.-Y. Chen, H.-M. Soo, S.-Q. Mok, A. Jamuth, N. Foxworth and M. Elbl for technical assistance. This research was funded by the Biomedical Research Council, Agency for Science, Technology and Research, Singapore. J.L.W. acknowledges support from US National Institutes of Health/National Eye Institute grants (NIH/NEI R01 EY020928 and NIH/NEI P30 EY014104). S.W.M.J. acknowledges support from grant EY11721 from the US National Institutes of Health/National Eye Institute and is an investigator of the Howard Hughes Medical Institute. L.R.P. acknowledges support from a Harvard Medical School Distinguished Ophthalmology Scholar Award and the Harvard Glaucoma Center of Excellence. J.H.F. acknowledges support from US National Institutes of Health/National Eye Institute grants (EY023512 and EY018825). Z.Y. acknowledges support from the National Natural Science Foundation of China (81025006 and 81170883), as well as from the Department of Science and Technology of Sichuan Province, China (2012SZ0219 and 2011jtd0020). M.S. acknowledges support from Robert Bosch Stiftung (Stuttgart, Germany) and the German Cancer Consortium (DKTK), Germany. The Australian case cohort was funded by grants from the Ophthalmic Research Institute of Australia and National Health and Medical Research Council (NHMRC) project 535044. The Thessaloniki Eye Study was cofunded by the European Union (European Social Fund) and Greek national funds under act {\textquoteleft}Aristia{\textquoteright} of the operational program {\textquoteleft}Education and Lifelong Learning{\textquoteright} (Supplementary Note). Blue Mountains Eye Study (BMES) GWAS and genotyping costs were supported by the Australian NHMRC (Canberra, Australia; NHMRC project grants 512423, 475604 and 529912) and the Wellcome Trust, UK, as part of the Wellcome Trust Case Control Consortium 2 (A. Viswanathan, P. McGuffin, P. Mitchell, F. Topouzis, P. Foster; grants 085475/B/ 08/Z and 085475/08/Z). K.P.B. is an NHMRC Senior Research Fellow, and J.E.C. is an NHMRC Practitioner Fellow. M.A.B. is an NHMRC Principal Research Fellow. A.W.H. is an NHMRC Peter Doherty Fellow. Publisher Copyright: {\textcopyright} 2015 Nature America, Inc. All rights reserved.",

year = "2015",

month = apr,

day = "28",

doi = "10.1038/ng.3226",

language = "English (US)",

volume = "47",

pages = "387--392",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "4",

}

TY - JOUR

T1 - A common variant mapping to CACNA1A is associated with susceptibility to exfoliation syndrome

AU - Aung, Tin

AU - Ozaki, Mineo

AU - Mizoguchi, Takanori

AU - Allingham, R. Rand

AU - Li, Zheng

AU - Haripriya, Aravind

AU - Nakano, Satoko

AU - Uebe, Steffen

AU - Harder, Jeffrey M.

AU - Chan, Anita S.Y.

AU - Lee, Mei Chin

AU - Burdon, Kathryn P.

AU - Astakhov, Yury S.

AU - Abu-Amero, Khaled K.

AU - Zenteno, Juan C.

AU - Nilgün, Yildirim

AU - Zarnowski, Tomasz

AU - Pakravan, Mohammad

AU - Safieh, Leen Abu

AU - Jia, Liyun

AU - Wang, Ya Xing

AU - Williams, Susan

AU - Paoli, Daniela

AU - Schlottmann, Patricio G.

AU - Huang, Lulin

AU - Sim, Kar Seng

AU - Foo, Jia Nee

AU - Nakano, Masakazu

AU - Ikeda, Yoko

AU - Kumar, Rajesh S.

AU - Ueno, Morio

AU - Manabe, Shin Ichi

AU - Hayashi, Ken

AU - Kazama, Shigeyasu

AU - Ideta, Ryuichi

AU - Mori, Yosai

AU - Miyata, Kazunori

AU - Sugiyama, Kazuhisa

AU - Higashide, Tomomi

AU - Chihara, Etsuo

AU - Inoue, Kenji

AU - Ishiko, Satoshi

AU - Yoshida, Akitoshi

AU - Yanagi, Masahide

AU - Kiuchi, Yoshiaki

AU - Aihara, Makoto

AU - Ohashi, Tsutomu

AU - Sakurai, Toshiya

AU - Sugimoto, Takako

AU - Chuman, Hideki

AU - Matsuda, Fumihiko

AU - Yamashiro, Kenji

AU - Gotoh, Norimoto

AU - Miyake, Masahiro

AU - Astakhov, Sergei Y.

AU - Osman, Essam A.

AU - Al-Obeidan, Saleh A.

AU - Owaidhah, Ohoud

AU - Al-Jasim, Leyla

AU - Shahwan, Sami Al

AU - Fogarty, Rhys A.

AU - Leo, Paul

AU - Yetkin, Yaz

AU - Ouz, Çilingir

AU - Kanavi, Mozhgan Rezaei

AU - Beni, Afsaneh Nederi

AU - Yazdani, Shahin

AU - Akopov, Evgeny L.

AU - Toh, Kai Yee

AU - Howell, Gareth R.

AU - Orr, Andrew C.

AU - Goh, Yufen

AU - Meah, Wee Yang

AU - Peh, Su Qin

AU - Kosior-Jarecka, Ewa

AU - Lukasik, Urszula

AU - Krumbiegel, Mandy

AU - Vithana, Eranga N.

AU - Wong, Tien Yin

AU - Liu, Yutao

AU - Koch, Allison E.Ashley

AU - Challa, Pratap

AU - Rautenbach, Robyn M.

AU - Mackey, David A.

AU - Hewitt, Alex W.

AU - Mitchell, Paul

AU - Wang, Jie Jin

AU - Ziskind, Ari

AU - Carmichael, Trevor

AU - Ramakrishnan, Rangappa

AU - Narendran, Kalpana

AU - Venkatesh, Rangaraj

AU - Vijayan, Saravanan

AU - Zhao, Peiquan

AU - Chen, Xueyi

AU - Guadarrama-Vallejo, Dalia

AU - Cheng, Ching Yu

AU - Perera, Shamira A.

AU - Husain, Rahat

AU - Ho, Su Ling

AU - Welge-Luessen, Ulrich Christoph

AU - Mardin, Christian

AU - Schloetzer-Schrehardt, Ursula

AU - Hillmer, Axel M.

AU - Herms, Stefan

AU - Moebus, Susanne

AU - Nöthen, Markus M.

AU - Weisschuh, Nicole

AU - Shetty, Rohit

AU - Ghosh, Arkasubhra

AU - Teo, Yik Ying

AU - Brown, Matthew A.

AU - Lischinsky, Ignacio

AU - Crowston, Jonathan G.

AU - Coote, Michael

AU - Zhao, Bowen

AU - Sang, Jinghong

AU - Zhang, Nihong

AU - You, Qisheng

AU - Vysochinskaya, Vera

AU - Founti, Panayiota

AU - Chatzikyriakidou, Anthoula

AU - Lambropoulos, Alexandros

AU - Anastasopoulos, Eleftherios

AU - Coleman, Anne L.

AU - Wilson, M. Roy

AU - Rhee, Douglas J.

AU - Kang, Jae Hee

AU - May-Bolchakova, Inna

AU - Heegaard, Steffen

AU - Mori, Kazuhiko

AU - Alward, Wallace L.M.

AU - Jonas, Jost B.

AU - Xu, Liang

AU - Liebmann, Jeffrey M.

AU - Chowbay, Balram

AU - Schaeffeler, Elke

AU - Schwab, Matthias

AU - Lerner, Fabian

AU - Wang, Ningli

AU - Yang, Zhenglin

AU - Frezzotti, Paolo

AU - Kinoshita, Shigeru

AU - Fingert, John H.

AU - Inatani, Masaru

AU - Tashiro, Kei

AU - Reis, André

AU - Edward, Deepak P.

AU - Pasquale, Louis R.

AU - Kubota, Toshiaki

AU - Wiggs, Janey L.

AU - Pasutto, Francesca

AU - Topouzis, Fotis

AU - Dubina, Michael

AU - Craig, Jamie E.

AU - Yoshimura, Nagahisa

AU - Sundaresan, Periasamy

AU - John, Simon W.M.

AU - Ritch, Robert

AU - Hauser, Michael A.

AU - Khor, Chiea Chuen

N1 - Funding Information: The authors thank the staff and participants of all studies for their important contributions. We thank K.-K. Heng, X.-Y. Chen, H.-M. Soo, S.-Q. Mok, A. Jamuth, N. Foxworth and M. Elbl for technical assistance. This research was funded by the Biomedical Research Council, Agency for Science, Technology and Research, Singapore. J.L.W. acknowledges support from US National Institutes of Health/National Eye Institute grants (NIH/NEI R01 EY020928 and NIH/NEI P30 EY014104). S.W.M.J. acknowledges support from grant EY11721 from the US National Institutes of Health/National Eye Institute and is an investigator of the Howard Hughes Medical Institute. L.R.P. acknowledges support from a Harvard Medical School Distinguished Ophthalmology Scholar Award and the Harvard Glaucoma Center of Excellence. J.H.F. acknowledges support from US National Institutes of Health/National Eye Institute grants (EY023512 and EY018825). Z.Y. acknowledges support from the National Natural Science Foundation of China (81025006 and 81170883), as well as from the Department of Science and Technology of Sichuan Province, China (2012SZ0219 and 2011jtd0020). M.S. acknowledges support from Robert Bosch Stiftung (Stuttgart, Germany) and the German Cancer Consortium (DKTK), Germany. The Australian case cohort was funded by grants from the Ophthalmic Research Institute of Australia and National Health and Medical Research Council (NHMRC) project 535044. The Thessaloniki Eye Study was cofunded by the European Union (European Social Fund) and Greek national funds under act ‘Aristia’ of the operational program ‘Education and Lifelong Learning’ (Supplementary Note). Blue Mountains Eye Study (BMES) GWAS and genotyping costs were supported by the Australian NHMRC (Canberra, Australia; NHMRC project grants 512423, 475604 and 529912) and the Wellcome Trust, UK, as part of the Wellcome Trust Case Control Consortium 2 (A. Viswanathan, P. McGuffin, P. Mitchell, F. Topouzis, P. Foster; grants 085475/B/ 08/Z and 085475/08/Z). K.P.B. is an NHMRC Senior Research Fellow, and J.E.C. is an NHMRC Practitioner Fellow. M.A.B. is an NHMRC Principal Research Fellow. A.W.H. is an NHMRC Peter Doherty Fellow. Publisher Copyright: © 2015 Nature America, Inc. All rights reserved.

PY - 2015/4/28

Y1 - 2015/4/28

N2 - 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 â '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.

AB - 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 â '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.

UR - http://www.scopus.com/inward/record.url?scp=84941616197&partnerID=8YFLogxK

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U2 - 10.1038/ng.3226

DO - 10.1038/ng.3226

M3 - Article

C2 - 25706626

AN - SCOPUS:84941616197

SN - 1061-4036

VL - 47

SP - 387

EP - 392

JO - Nature Genetics

JF - Nature Genetics

IS - 4

ER -

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

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