Genetic association study of exfoliation syndrome identifies a protective rare variant at LOXL1 and five new susceptibility loci

Tin Aung; Mineo Ozaki; Mei Chin Lee; Ursula Schlotzer-Schrehardt; Gudmar Thorleifsson; Takanori Mizoguchi; Robert P. Igo; Aravind Haripriya; Susan E. Williams; Yury S. Astakhov; Andrew C. Orr; Kathryn P. Burdon; Satoko Nakano; Kazuhiko Mori; Khaled Abu-Amero; Michael Hauser; Zheng Li; Gopalakrishnan Prakadeeswari; Jessica N. Cooke Bailey; Alina Popa Cherecheanu; Jae H. Kang; Sarah Nelson; Ken Hayashi; Shin-ichi Manabe; Shigeyasu Kazama; Tomasz Zarnowski; Kenji Inoue; Murat Irkec; Miguel Coca-Prados; Kazuhisa Sugiyama; Irma Jarvela; Patricio Schlottmann; S. Fabian Lerner; Hasnaa Lamari; Yildirim Nilgun; Mukharram Bikbov; Ki Ho Park; Soon Cheol Cha; Kenji Yamashiro; Juan C. Zenteno; Jost B. Jonas; Rajesh S. Kumar; Shamira A. Perera; Anita S. Y. Chan; Nino Kobakhidze; Ronnie George; Lingam Vijaya; Tan Do; Rohit Shetty; Author collaboration

doi:10.1038/ng.3875

Genetic association study of exfoliation syndrome identifies a protective rare variant at LOXL1 and five new susceptibility loci

Tin Aung^*, Mineo Ozaki, Mei Chin Lee, Ursula Schlotzer-Schrehardt, Gudmar Thorleifsson, Takanori Mizoguchi, Robert P. Igo, Aravind Haripriya, Susan E. Williams, Yury S. Astakhov, Andrew C. Orr, Kathryn P. Burdon, Satoko Nakano, Kazuhiko Mori, Khaled Abu-Amero, Michael Hauser, Zheng Li, Gopalakrishnan Prakadeeswari, Jessica N. Cooke Bailey, Alina Popa CherecheanuJae H. Kang, Sarah Nelson, Ken Hayashi, Shin-ichi Manabe, Shigeyasu Kazama, Tomasz Zarnowski, Kenji Inoue, Murat Irkec, Miguel Coca-Prados, Kazuhisa Sugiyama, Irma Jarvela, Patricio Schlottmann, S. Fabian Lerner, Hasnaa Lamari, Yildirim Nilgun, Mukharram Bikbov, Ki Ho Park, Soon Cheol Cha, Kenji Yamashiro, Juan C. Zenteno, Jost B. Jonas, Rajesh S. Kumar, Shamira A. Perera, Anita S. Y. Chan, Nino Kobakhidze, Ronnie George, Lingam Vijaya, Tan Do, Rohit Shetty, Author collaboration

^*Corresponding author for this work

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

Abstract

Exfoliation syndrome (XFS) is the most common known risk factor for secondary glaucoma and a major cause of blindness worldwide. Variants in two genes, LOXL1 and CACNA1A, have previously been associated with XFS. To further elucidate the genetic basis of XFS, we collected a global sample of XFS cases to refine the association at LOXL1, which previously showed inconsistent results across populations, and to identify new variants associated with XFS. We identified a rare protective allele at LOXL1 (p.Phe407, odds ratio (OR) = 25, P = 2.9 x 10(-14)) through deep resequencing of XFS cases and controls from nine countries. A genome-wide association study (GWAS) of XFS cases and controls from 24 countries followed by replication in 18 countries identified seven genome-wide significant loci (P < 5 x 10(-8)). We identified association signals at 13q12 (POMP), 11q23.3 (TMEM136), 6p21 (AGPAT1), 3p24 (RBMS3) and 5q23 (near SEMA6A). These findings provide biological insights into the pathology of XFS and highlight a potential role for naturally occurring rare LOXL1 variants in disease biology.

Original language	English
Pages (from-to)	993-1004
Number of pages	15
Journal	Nature Genetics
Volume	49
Issue number	7
DOIs	https://doi.org/10.1038/ng.3875
Publication status	Published - Jul 2017

Keywords

Genome-wide association
Inflammatory-bowel-disease
Common sequence variants
Risk loci
Pseudoexfoliation syndrome
Blood-pressure
Glaucoma
Metaanalysis
Polymorphisms
Individuals

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Aung, T., Ozaki, M., Lee, M. C., Schlotzer-Schrehardt, U., Thorleifsson, G., Mizoguchi, T., Igo, R. P., Haripriya, A., Williams, S. E., Astakhov, Y. S., Orr, A. C., Burdon, K. P., Nakano, S., Mori, K., Abu-Amero, K., Hauser, M., Li, Z., Prakadeeswari, G., Bailey, J. N. C., ... Author collaboration (2017). Genetic association study of exfoliation syndrome identifies a protective rare variant at LOXL1 and five new susceptibility loci. Nature Genetics, 49(7), 993-1004. https://doi.org/10.1038/ng.3875

@article{835b154dac3b416ea7a108a94e5570d8,

title = "Genetic association study of exfoliation syndrome identifies a protective rare variant at LOXL1 and five new susceptibility loci",

abstract = "Exfoliation syndrome (XFS) is the most common known risk factor for secondary glaucoma and a major cause of blindness worldwide. Variants in two genes, LOXL1 and CACNA1A, have previously been associated with XFS. To further elucidate the genetic basis of XFS, we collected a global sample of XFS cases to refine the association at LOXL1, which previously showed inconsistent results across populations, and to identify new variants associated with XFS. We identified a rare protective allele at LOXL1 (p.Phe407, odds ratio (OR) = 25, P = 2.9 x 10(-14)) through deep resequencing of XFS cases and controls from nine countries. A genome-wide association study (GWAS) of XFS cases and controls from 24 countries followed by replication in 18 countries identified seven genome-wide significant loci (P < 5 x 10(-8)). We identified association signals at 13q12 (POMP), 11q23.3 (TMEM136), 6p21 (AGPAT1), 3p24 (RBMS3) and 5q23 (near SEMA6A). These findings provide biological insights into the pathology of XFS and highlight a potential role for naturally occurring rare LOXL1 variants in disease biology.",

keywords = "Genome-wide association, Inflammatory-bowel-disease, Common sequence variants, Risk loci, Pseudoexfoliation syndrome, Blood-pressure, Glaucoma, Metaanalysis, Polymorphisms, Individuals",

author = "Tin Aung and Mineo Ozaki and Lee, {Mei Chin} and Ursula Schlotzer-Schrehardt and Gudmar Thorleifsson and Takanori Mizoguchi and Igo, {Robert P.} and Aravind Haripriya and Williams, {Susan E.} and Astakhov, {Yury S.} and Orr, {Andrew C.} and Burdon, {Kathryn P.} and Satoko Nakano and Kazuhiko Mori and Khaled Abu-Amero and Michael Hauser and Zheng Li and Gopalakrishnan Prakadeeswari and Bailey, {Jessica N. Cooke} and Cherecheanu, {Alina Popa} and Kang, {Jae H.} and Sarah Nelson and Ken Hayashi and Shin-ichi Manabe and Shigeyasu Kazama and Tomasz Zarnowski and Kenji Inoue and Murat Irkec and Miguel Coca-Prados and Kazuhisa Sugiyama and Irma Jarvela and Patricio Schlottmann and Lerner, {S. Fabian} and Hasnaa Lamari and Yildirim Nilgun and Mukharram Bikbov and Park, {Ki Ho} and Cha, {Soon Cheol} and Kenji Yamashiro and Zenteno, {Juan C.} and Jonas, {Jost B.} and Kumar, {Rajesh S.} and Perera, {Shamira A.} and Chan, {Anita S. Y.} and Nino Kobakhidze and Ronnie George and Lingam Vijaya and Tan Do and Rohit Shetty and {Author collaboration}",

year = "2017",

month = jul,

doi = "10.1038/ng.3875",

language = "English",

volume = "49",

pages = "993--1004",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "7",

}

Aung, T, Ozaki, M, Lee, MC, Schlotzer-Schrehardt, U, Thorleifsson, G, Mizoguchi, T, Igo, RP, Haripriya, A, Williams, SE, Astakhov, YS, Orr, AC, Burdon, KP, Nakano, S, Mori, K, Abu-Amero, K, Hauser, M, Li, Z, Prakadeeswari, G, Bailey, JNC, Cherecheanu, AP, Kang, JH, Nelson, S, Hayashi, K, Manabe, S, Kazama, S, Zarnowski, T, Inoue, K, Irkec, M, Coca-Prados, M, Sugiyama, K, Jarvela, I, Schlottmann, P, Lerner, SF, Lamari, H, Nilgun, Y, Bikbov, M, Park, KH, Cha, SC, Yamashiro, K, Zenteno, JC, Jonas, JB, Kumar, RS, Perera, SA, Chan, ASY, Kobakhidze, N, George, R, Vijaya, L, Do, T, Shetty, R & Author collaboration 2017, 'Genetic association study of exfoliation syndrome identifies a protective rare variant at LOXL1 and five new susceptibility loci', Nature Genetics, vol. 49, no. 7, pp. 993-1004. https://doi.org/10.1038/ng.3875

TY - JOUR

T1 - Genetic association study of exfoliation syndrome identifies a protective rare variant at LOXL1 and five new susceptibility loci

AU - Aung, Tin

AU - Ozaki, Mineo

AU - Lee, Mei Chin

AU - Schlotzer-Schrehardt, Ursula

AU - Thorleifsson, Gudmar

AU - Mizoguchi, Takanori

AU - Igo, Robert P.

AU - Haripriya, Aravind

AU - Williams, Susan E.

AU - Astakhov, Yury S.

AU - Orr, Andrew C.

AU - Burdon, Kathryn P.

AU - Nakano, Satoko

AU - Mori, Kazuhiko

AU - Abu-Amero, Khaled

AU - Hauser, Michael

AU - Li, Zheng

AU - Prakadeeswari, Gopalakrishnan

AU - Bailey, Jessica N. Cooke

AU - Cherecheanu, Alina Popa

AU - Kang, Jae H.

AU - Nelson, Sarah

AU - Hayashi, Ken

AU - Manabe, Shin-ichi

AU - Kazama, Shigeyasu

AU - Zarnowski, Tomasz

AU - Inoue, Kenji

AU - Irkec, Murat

AU - Coca-Prados, Miguel

AU - Sugiyama, Kazuhisa

AU - Jarvela, Irma

AU - Schlottmann, Patricio

AU - Lerner, S. Fabian

AU - Lamari, Hasnaa

AU - Nilgun, Yildirim

AU - Bikbov, Mukharram

AU - Park, Ki Ho

AU - Cha, Soon Cheol

AU - Yamashiro, Kenji

AU - Zenteno, Juan C.

AU - Jonas, Jost B.

AU - Kumar, Rajesh S.

AU - Perera, Shamira A.

AU - Chan, Anita S. Y.

AU - Kobakhidze, Nino

AU - George, Ronnie

AU - Vijaya, Lingam

AU - Do, Tan

AU - Shetty, Rohit

AU - Author collaboration

PY - 2017/7

Y1 - 2017/7

N2 - Exfoliation syndrome (XFS) is the most common known risk factor for secondary glaucoma and a major cause of blindness worldwide. Variants in two genes, LOXL1 and CACNA1A, have previously been associated with XFS. To further elucidate the genetic basis of XFS, we collected a global sample of XFS cases to refine the association at LOXL1, which previously showed inconsistent results across populations, and to identify new variants associated with XFS. We identified a rare protective allele at LOXL1 (p.Phe407, odds ratio (OR) = 25, P = 2.9 x 10(-14)) through deep resequencing of XFS cases and controls from nine countries. A genome-wide association study (GWAS) of XFS cases and controls from 24 countries followed by replication in 18 countries identified seven genome-wide significant loci (P < 5 x 10(-8)). We identified association signals at 13q12 (POMP), 11q23.3 (TMEM136), 6p21 (AGPAT1), 3p24 (RBMS3) and 5q23 (near SEMA6A). These findings provide biological insights into the pathology of XFS and highlight a potential role for naturally occurring rare LOXL1 variants in disease biology.

AB - Exfoliation syndrome (XFS) is the most common known risk factor for secondary glaucoma and a major cause of blindness worldwide. Variants in two genes, LOXL1 and CACNA1A, have previously been associated with XFS. To further elucidate the genetic basis of XFS, we collected a global sample of XFS cases to refine the association at LOXL1, which previously showed inconsistent results across populations, and to identify new variants associated with XFS. We identified a rare protective allele at LOXL1 (p.Phe407, odds ratio (OR) = 25, P = 2.9 x 10(-14)) through deep resequencing of XFS cases and controls from nine countries. A genome-wide association study (GWAS) of XFS cases and controls from 24 countries followed by replication in 18 countries identified seven genome-wide significant loci (P < 5 x 10(-8)). We identified association signals at 13q12 (POMP), 11q23.3 (TMEM136), 6p21 (AGPAT1), 3p24 (RBMS3) and 5q23 (near SEMA6A). These findings provide biological insights into the pathology of XFS and highlight a potential role for naturally occurring rare LOXL1 variants in disease biology.

KW - Genome-wide association

KW - Inflammatory-bowel-disease

KW - Common sequence variants

KW - Risk loci

KW - Pseudoexfoliation syndrome

KW - Blood-pressure

KW - Glaucoma

KW - Metaanalysis

KW - Polymorphisms

KW - Individuals

U2 - 10.1038/ng.3875

DO - 10.1038/ng.3875

M3 - Article

C2 - 28553957

SN - 1061-4036

VL - 49

SP - 993

EP - 1004

JO - Nature Genetics

JF - Nature Genetics

IS - 7

ER -

Genetic association study of exfoliation syndrome identifies a protective rare variant at LOXL1 and five new susceptibility loci

Abstract

Keywords

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