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 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; Steffen Heegaard; Blue Mountains Eye Study GWAS Team; Steffen Heegaard

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 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, Steffen Heegaard, Blue Mountains Eye Study GWAS Team, Steffen Heegaard

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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.

Originalsprog	Engelsk
Tidsskrift	Nature Genetics
Vol/bind	47
Udgave nummer	4
Sider (fra-til)	387-92
Antal sider	6
ISSN	1061-4036
DOI	https://doi.org/10.1038/ng.3226
Status	Udgivet - apr. 2015

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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., ... Heegaard, S. (2015). A common variant mapping to CACNA1A is associated with susceptibility to exfoliation syndrome. Nature Genetics, 47(4), 387-92. 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, R, 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, Heegaard, S, Blue Mountains Eye Study GWAS Team & Heegaard, S 2015, 'A common variant mapping to CACNA1A is associated with susceptibility to exfoliation syndrome', Nature Genetics, bind 47, nr. 4, s. 387-92. https://doi.org/10.1038/ng.3226

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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(-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.",

keywords = "Animals, Asian Continental Ancestry Group, Calcium Channels, Case-Control Studies, Chromosome Mapping, Exfoliation Syndrome, Genetic Predisposition to Disease, Genome-Wide Association Study, Glaucoma, Open-Angle, HEK293 Cells, HeLa Cells, Humans, Japan, MCF-7 Cells, Mice, Mice, Inbred C57BL, Polymorphism, Single Nucleotide, Tumor Cells, Cultured",

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 Rajesh Kumar and Morio Ueno and Shin-ichi Manabe 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 Steffen Heegaard and \{Blue Mountains Eye Study GWAS Team\} and Steffen Heegaard",

year = "2015",

month = apr,

doi = "10.1038/ng.3226",

language = "English",

volume = "47",

pages = "387--92",

journal = "Nature Genetics",

issn = "1061-4036",

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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

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 - Heegaard, Steffen

AU - Blue Mountains Eye Study GWAS Team

AU - Heegaard, Steffen

PY - 2015/4

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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(-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(-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.

KW - Animals

KW - Asian Continental Ancestry Group

KW - Calcium Channels

KW - Case-Control Studies

KW - Chromosome Mapping

KW - Exfoliation Syndrome

KW - Genetic Predisposition to Disease

KW - Genome-Wide Association Study

KW - Glaucoma, Open-Angle

KW - HEK293 Cells

KW - HeLa Cells

KW - Humans

KW - Japan

KW - MCF-7 Cells

KW - Mice

KW - Mice, Inbred C57BL

KW - Polymorphism, Single Nucleotide

KW - Tumor Cells, Cultured

UR - https://www.scopus.com/pages/publications/84941616197

U2 - 10.1038/ng.3226

DO - 10.1038/ng.3226

M3 - Journal article

C2 - 25706626

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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