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 |
ASJC Scopus subject areas
- Genetics
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Genetic association study of exfoliation syndrome identifies a protective rare variant at LOXL1 and five new susceptibility loci. / Aung, Tin; Ozaki, Mineo; Lee, Mei Chin et al.
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
AU - Aung, Tin
AU - Ozaki, Mineo
AU - Lee, Mei Chin
AU - Schlötzer-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 - Järvelä, Irma
AU - Schlottmann, Patricio
AU - Lerner, S. Fabian
AU - Lamari, Hasnaa
AU - Nilgün, 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 - Edward, Deepak P.
AU - De Juan Marcos, Lourdes
AU - Pakravan, Mohammad
AU - Moghimi, Sasan
AU - Ideta, Ryuichi
AU - Bach-Holm, Daniella
AU - Kappelgaard, Per
AU - Wirostko, Barbara
AU - Thomas, Samuel
AU - Gaston, Daniel
AU - Bedard, Karen
AU - Greer, Wenda L.
AU - Yang, Zhenglin
AU - Chen, Xueyi
AU - Huang, Lulin
AU - Sang, Jinghong
AU - Jia, Hongyan
AU - Jia, Liyun
AU - Qiao, Chunyan
AU - Zhang, Hui
AU - Liu, Xuyang
AU - Zhao, Bowen
AU - Wang, Ya Xing
AU - Xu, Liang
AU - Leruez, Stéphanie
AU - Reynier, Pascal
AU - Chichua, George
AU - Tabagari, Sergo
AU - Uebe, Steffen
AU - Zenkel, Matthias
AU - Berner, Daniel
AU - Mossböck, Georg
AU - Weisschuh, Nicole
AU - Hoja, Ursula
AU - Welge-Luessen, Ulrich Christoph
AU - Mardin, Christian
AU - Founti, Panayiota
AU - Chatzikyriakidou, Anthi
AU - Pappas, Theofanis
AU - Anastasopoulos, Eleftherios
AU - Lambropoulos, Alexandros
AU - Ghosh, Arkasubhra
AU - Shetty, Rohit
AU - Porporato, Natalia
AU - Saravanan, Vijayan
AU - Venkatesh, Rengaraj
AU - Shivkumar, Chandrashekaran
AU - Kalpana, Narendran
AU - Sarangapani, Sripriya
AU - Kanavi, Mozhgan R.
AU - Beni, Afsaneh Naderi
AU - Yazdani, Shahin
AU - Lashay, Alireza
AU - Naderifar, Homa
AU - Khatibi, Nassim
AU - Fea, Antonio
AU - Lavia, Carlo
AU - Dallorto, Laura
AU - Rolle, Teresa
AU - Frezzotti, Paolo
AU - Paoli, Daniela
AU - Salvi, Erika
AU - Manunta, Paolo
AU - Mori, Yosai
AU - Miyata, Kazunori
AU - Higashide, Tomomi
AU - Chihara, Etsuo
AU - Ishiko, Satoshi
AU - Yoshida, Akitoshi
AU - Yanagi, Masahide
AU - Kiuchi, Yoshiaki
AU - Ohashi, Tsutomu
AU - Sakurai, Toshiya
AU - Sugimoto, Takako
AU - Chuman, Hideki
AU - Aihara, Makoto
AU - Inatani, Masaru
AU - Miyake, Masahiro
AU - Gotoh, Norimoto
AU - Matsuda, Fumihiko
AU - Yoshimura, Nagahisa
AU - Ikeda, Yoko
AU - Ueno, Morio
AU - Sotozono, Chie
AU - Jeoung, Jin Wook
AU - Sagong, Min
AU - Park, Kyu Hyung
AU - Ahn, Jeeyun
AU - Cruz-Aguilar, Marisa
AU - Ezzouhairi, Sidi M.
AU - Rafei, Abderrahman
AU - Chong, Yaan Fun
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AU - Goh, Shuang Ru
AU - Chen, Yueming
AU - Yong, Victor H.K.
AU - Khan, Muhammad Imran
AU - Olawoye, Olusola O.
AU - Ashaye, Adeyinka O.
AU - Ugbede, Idakwo
AU - Onakoya, Adeola
AU - Kizor-Akaraiwe, Nkiru
AU - Teekhasaenee, Chaiwat
AU - Suwan, Yanin
AU - Supakontanasan, Wasu
AU - Okeke, Suhanya
AU - Uche, Nkechi J.
AU - Asimadu, Ifeoma
AU - Ayub, Humaira
AU - Akhtar, Farah
AU - Kosior-Jarecka, Ewa
AU - Lukasik, Urszula
AU - Lischinsky, Ignacio
AU - Castro, Vania
AU - Grossmann, Rodolfo Perez
AU - Megevand, Gordana Sunaric
AU - Roy, Sylvain
AU - Dervan, Edward
AU - Silke, Eoin
AU - Rao, Aparna
AU - Sahay, Priti
AU - Fornero, Pablo
AU - Cuello, Osvaldo
AU - Sivori, Delia
AU - Zompa, Tamara
AU - Mills, Richard A.
AU - Souzeau, Emmanuelle
AU - Mitchell, Paul
AU - Wang, Jie Jin
AU - Hewitt, Alex W.
AU - Coote, Michael
AU - Crowston, Jonathan G.
AU - Astakhov, Sergei Y.
AU - Akopov, Eugeny L.
AU - Emelyanov, Anton
AU - Vysochinskaya, Vera
AU - Kazakbaeva, Gyulli
AU - Fayzrakhmanov, Rinat
AU - Al-Obeidan, Saleh A.
AU - Owaidhah, Ohoud
AU - Aljasim, Leyla Ali
AU - Chowbay, Balram
AU - Foo, Jia Nee
AU - Soh, Raphael Q.
AU - Sim, Kar Seng
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
AU - Husain, Rahat
AU - Ho, Su Ling
AU - Hillmer, Axel M.
AU - Cheng, Ching Yu
AU - Escudero-Domínguez, Francisco A.
AU - González-Sarmiento, Rogelio
AU - Martinon-Torres, Frederico
AU - Salas, Antonio
AU - Pathanapitoon, Kessara
AU - Hansapinyo, Linda
AU - Wanichwecharugruang, Boonsong
AU - Kitnarong, Naris
AU - Sakuntabhai, Anavaj
AU - Nguyn, Hip X.
AU - Nguyn, Giang T.T.
AU - Nguyn, Trình V.
AU - Zenz, Werner
AU - Binder, Alexander
AU - Klobassa, Daniela S.
AU - Hibberd, Martin L.
AU - Davila, Sonia
AU - Herms, Stefan
AU - Nöthen, Markus M.
AU - Moebus, Susanne
AU - Rautenbach, Robyn M.
AU - Ziskind, Ari
AU - Carmichael, Trevor R.
AU - Ramsay, Michele
AU - Álvarez, Lydia
AU - García, Montserrat
AU - González-Iglesias, Héctor
AU - Rodríguez-Calvo, Pedro P.
AU - Cueto, Luis Fernández Vega
AU - Oguz, Çilingir
AU - Tamcelik, Nevbahar
AU - Atalay, Eray
AU - Batu, Bilge
AU - Aktas, Dilek
AU - Kaslm, Burcu
AU - Wilson, M. Roy
AU - Coleman, Anne L.
AU - Liu, Yutao
AU - Challa, Pratap
AU - Herndon, Leon
AU - Kuchtey, Rachel W.
AU - Kuchtey, John
AU - Curtin, Karen
AU - Chaya, Craig J.
AU - Crandall, Alan
AU - Zangwill, Linda M.
AU - Wong, Tien Yin
AU - Nakano, Masakazu
AU - Kinoshita, Shigeru
AU - Den Hollander, Anneke I.
AU - Vesti, Eija
AU - Fingert, John H.
AU - Lee, Richard K.
AU - Sit, Arthur J.
AU - Shingleton, Bradford J.
AU - Wang, Ningli
AU - Cusi, Daniele
AU - Qamar, Raheel
AU - Kraft, Peter
AU - Pericak-Vance, Margaret A.
AU - Raychaudhuri, Soumya
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
AU - Allingham, R. Rand
AU - Milea, Dan
AU - Ritch, Robert
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
AU - Stefansson, Kari
AU - Wiggs, Janey L.
AU - Pasutto, Francesca
AU - Khor, Chiea Chuen
N1 - Funding Information: This research is supported by the Biomedical Research Council, Agency for Science, Technology and Research, Singapore (to C.C.K.), by the Glaucoma Foundation of New York (to C.C.K.), by grants from the National Medical Research Council, Singapore NMRC/TCR/008-SERI/2013 and NMRC/STAR/0023/2014 to T.A. and NMRC/CBRG/0032/2013 to E.N.V.), by the Interdisziplinäres Zentrum für Klinische Forschung (IZKF-E23) from Germany to F.P. and U.S.-S., and by grants from the US National Institutes of Health: UM1 CA186107, R01 CA49449, R01 AR056291, R01 CA131332, P01 CA055075, R01 CA134958 and R01 EY015473 to J.L.W. For XFS cases in the US GWAS data set, genotyping services were provided through a grant to J.L.W. (HG008597) by the Center for Inherited Disease Research (CIDR). CIDR is fully funded through a federal contract from the US National Institutes of Health to The Johns Hopkins University, contract HHSN268201200008I. The Beijing, China, collection was supported by funding from the National Natural Science Foundation of China (81030016 and 81570837), the Program of Beijing Scholars (2013), the National Major Scientific and Technological Special Project for Significant New Drugs Development (2011ZX09302-007-05) and Leading Talents-High-Level Talents of the Health System of Beijing (2009-1-05) to N. Wang. We dedicate this article to the ophthalmologist Eva Forsman from Finland who passed away after diagnosing all of the exfoliation syndrome cases from Finland. 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 -