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 × 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 × 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 (US) |
---|---|
Pages (from-to) | 993-1004 |
Number of pages | 12 |
Journal | Nature Genetics |
Volume | 49 |
Issue number | 7 |
DOIs | |
State | Published - Jul 1 2017 |
Externally published | Yes |
ASJC Scopus subject areas
- Genetics
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In: Nature Genetics, Vol. 49, No. 7, 01.07.2017, p. 993-1004.
Research output: Contribution to journal › Article › peer-review
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TY - JOUR
T1 - Genetic association study of exfoliation syndrome identifies a protective rare variant at LOXL1 and five new susceptibility loci
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AU - Lischinsky, Ignacio
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AU - Megevand, Gordana Sunaric
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AU - Kazakbaeva, Gyulli
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AU - Aljasim, Leyla Ali
AU - Chowbay, Balram
AU - Foo, Jia Nee
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AU - Xie, Zhicheng
AU - Cheong, Augustine W.O.
AU - Mok, Shi Qi
AU - Soo, Hui Meng
AU - Chen, Xiao Yin
AU - Peh, Su Qin
AU - Heng, Khai Koon
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AU - Ho, Su Ling
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AU - Cheng, Ching Yu
AU - Escudero-Domínguez, Francisco A.
AU - González-Sarmiento, Rogelio
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AU - Pathanapitoon, Kessara
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AU - Wanichwecharugruang, Boonsong
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AU - Crandall, Alan
AU - Zangwill, Linda M.
AU - Wong, Tien Yin
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AU - Kinoshita, Shigeru
AU - Den Hollander, Anneke I.
AU - Vesti, Eija
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AU - Lee, Richard K.
AU - Sit, Arthur J.
AU - Shingleton, Bradford J.
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AU - Cusi, Daniele
AU - Qamar, Raheel
AU - Kraft, Peter
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AU - Heegaard, Steffen
AU - Kivelä, Tero
AU - Reis, André
AU - Kruse, Friedrich E.
AU - Weinreb, Robert N.
AU - Pasquale, Louis R.
AU - Haines, Jonathan L.
AU - Thorsteinsdottir, Unnur
AU - Jonasson, Fridbert
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AU - Kubota, Toshiaki
AU - Tashiro, Kei
AU - Vithana, Eranga N.
AU - Micheal, Shazia
AU - Topouzis, Fotis
AU - Craig, Jamie E.
AU - Dubina, Michael
AU - Sundaresan, Periasamy
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N1 - Publisher Copyright: © 2017 Nature America, Inc., part of Springer Nature. All rights reserved.
PY - 2017/7/1
Y1 - 2017/7/1
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 × 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 × 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 × 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 × 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.
UR - http://www.scopus.com/inward/record.url?scp=85021706287&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85021706287&partnerID=8YFLogxK
U2 - 10.1038/ng.3875
DO - 10.1038/ng.3875
M3 - Article
C2 - 28553957
AN - SCOPUS:85021706287
SN - 1061-4036
VL - 49
SP - 993
EP - 1004
JO - Nature Genetics
JF - Nature Genetics
IS - 7
ER -