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 |
|---|---|
| Pages (from-to) | 993-1004 |
| Number of pages | 12 |
| Journal | Nature Genetics |
| Volume | 49 |
| Issue number | 7 |
| DOIs | |
| Publication status | Published - 1 Jul 2017 |
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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
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
AU - Schloetzer-Schrehardt, Ursula
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AU - Mizoguchi, Takanori
AU - Igo, Robert
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AU - de Juan Marcos, Lourdes
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AU - Thomas, Samual
AU - Gaston, Daniel
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AU - Pappas, Theofanis
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AU - Shivkumar, Chandrashekaran
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AU - Khan, Muhammad
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AU - Suwan, Yanin
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AU - Dervan, Edward
AU - Silke, Eoin
AU - Rao, Aparna
AU - Sahay, Priti
AU - Fornero, Pablo
AU - Cuello, Osvaldo
AU - Sivori, Delia
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AU - Vysochinskaya, Vera
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AU - Aljasim, Leyla
AU - Chowbay, Balram
AU - Foo, Jia-Nee
AU - Soh, Raphael
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AU - Xie, Zhicheng
AU - Cheong, Augustine
AU - Mok, Shi
AU - Soo, Hui
AU - Chen, Xiao
AU - Peh, Su Qin
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AU - Husain, Rahat
AU - Ho, Su-Ling
AU - Hillmer, Axel
AU - Cheng, Ching-Yu
AU - Escudero-Domínguez, Francisco
AU - González-Sarmiento, Rogelio
AU - Martinon-Torres, Frederico
AU - Salas, Antonio
AU - Pathanapitoon, Kessara
AU - Hansapinyo, Linda
AU - Wanichwecharugruang, Boonsong
AU - Kitnarong, Naris
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AU - Nguyn, Hip
AU - Nguyn, Giang
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AU - Klobassa, Daniela
AU - Hibberd, Martin
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AU - Herms, Stefan
AU - Nothen, Markus
AU - Moebus, Susanne
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AU - Alvarez, Lydia
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AU - Wilson, Roy
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AU - Liu, Yutao
AU - Challa, Pratap
AU - Herndon, Leon
AU - Kuchtey, Rachel
AU - Kuchtey, John
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AU - Chaya, Craig
AU - Crandall, Alan
AU - Zangwill, Linda
AU - Wong, Tien
AU - Nakano, Masakazu
AU - Kinoshita, Shigeru
AU - den Hollander, Anneke
AU - Vesti, Eija
AU - Fingert, John
AU - Lee, Richard
AU - Sit, Arthur
AU - Shingleton, Bradford
AU - Wang, Ningli
AU - Cusi, Daniele
AU - Qamar, Raheel
AU - Kraft, Peter
AU - Pericak-Vance, Margaret
AU - Raychaudhuri, S
AU - Heegaard, Steffen
AU - Kivela, Tero
AU - Reis, Andre
AU - Kruse, Friedrich
AU - Weinreb, Robert
AU - Pasquale, Louis
AU - Haines, Jonathan
AU - Thorsteinsdottir, Unnur
AU - Jonasson, Fridbert
AU - Allingham, R
AU - Milea, Dan
AU - Ritch, Robert
AU - Kubota, Toshiaki
AU - Tashiro, Kei
AU - Vithana, Eranga
AU - Michael, Shazia
AU - Topouzis, Fotis
AU - Craig, Jamie
AU - Dubina, Michael
AU - Sundaresan, Periasamy
AU - Stefansson, K
AU - Wiggs, Janey
AU - Pasutto, Francesca
AU - Khor, Chiea-Chuen
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
U2 - 10.1038/ng.3875
DO - 10.1038/ng.3875
M3 - Article
SN - 1061-4036
VL - 49
SP - 993
EP - 1004
JO - Nature Genetics
JF - Nature Genetics
IS - 7
ER -