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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Genetic association study of exfoliation syndrome identifies a protective rare variant at LOXL1 and five new susceptibility loci. / Aung, Tin; Ozaki, Mineo; Lee, Mei; Schloetzer-Schrehardt, Ursula; Thorleifsson, G; Mizoguchi, Takanori; Igo, Robert; Haripriya, Aravind; Williams, Susan; Astakhov, Yury; Orr, Andrew; Burdon, Kathryn; Nakano, Satoko; Mori, Kazuhiko; Abu-Amero, Khalid; Hauser, Michael; Li, Zheng; Prakadeeswari, Gopalakrishnan; Bailey, Jessica; Cherecheanu, Alina; Kang, Jae; Nelson, Sarah; Hayashi, Ken; Manabe, Shin-ichi; Kazama, Shigeyasu; Zarnowski, Tomasz; Inoue, Kenji; Irkec, Murat; Coca-Prados, Miguel; Sugiyama, Kazuhisa; Jarvela, Irma; Schlottmann, Patricio; Lerner, Fabian; Lamari, Hasnaa; Nilgun, Yildirim; Bikbov, Mukharram; Park, Ki-Ho; Cha, Soon; Yamashiro, Kenji; Zenteno, Juan; Jonas, Jost; Kumar, Rajesh; Perera, Shamira; Chan, Anita; Kobakhidze, Nino; George, Ronnie; Vijaya, Lingam; Do, Tan; Edward, Deepak; de Juan Marcos, Lourdes; Pakravan, Mohammad; Moghimi, Sasan; Ideta, Ryuichi; Bach-Holme, Daniella; Kappelgaard, Per; Wirostko, Barbara; Thomas, Samual; Gaston, Daniel; Bedard, Karen; Greer, Wenda; Yang, Zhenglin; Chen, Xueyi; Huang, Lulin; Sang, Jinghong; Jia, Hongyan; Jia, Liyun; Qiao, Chunyan; Zhang, Hui; Liu, Xuyang; Zhao, Bowen; Wang, Yaxing; Xu, Liang; Leruez, Stephanie; Reynier, Pascal; Chichua, George; Tabagari, Sergo; Uebe, Steffen; Zenkel, Matthias; Berner, Daniel; Mossbock, Georg; Weisschuh, Nicole; Hoja, Ursula; Welge-Luessen, Ulrich-Christoph; Mardin, Christian; Founti, Panayiota; Chatzikyriakidou, Anthoula; Pappas, Theofanis; Anastasopoulos, Eleftherios; Lambropoulos, Alexandros; Ghosh, Arkasubhra; Shetty, Rohit; Porporato, Natalia; Saravanan, Vijayan; Venkatesh, Rangaraj; Shivkumar, Chandrashekaran; Kalpana, Narendran; Sarangapani, Sripriya; Kanavi, Mozhgan; Beni, Afsaneh; Yazdani, Shahin; Lashay, Alireza; Naderifar, Homa; Khatibi, Nassim; Fea, Antonio; Lavia, Carlo; Dallorto, Laura; Rolle, Teresa; Frezzotti, Paolo; Paoli, Daniela; Salvi, Erika; Manunta, Paolo; Mori, Yosai; Miyata, K; Higashide, Tomomi; Chihara, Etsuo; Ishiko, Satoshi; Yoshida, Akitoshi; Kiuchi, Yoshiaki; Yanagi, Masahide; Ohashi, Tsutomu; Sakurai, Toshiya; Sugimoto, Takako; Chuman, Hideki; Aihara, Makoto; Inatani, Masaru; Miyake, Masahiro; Gotoh, Norimoto; Matsuda, Fumihiko; Yoshimura, Nagahisa; Ikeda, Yoko; Ueno, Morio; Sotozono, Chie; Jeoung, Jin; Sagong, Min; Park, Kyu; Ahn, Jeeyun; Cruz-Aguilar, Marisa; Ezzouhairi, Sidi; Rafei, Abderrahman; Chong, Yaan; Ng, Xiao; Goh, Shuang; Chen, Yueming; Yong, Victor; Khan, Muhammad; Olawoye, Olusola; Ashaye, Adeyinka; Ugbede, Idakwo; Onakoya, Adeola; Kizor-Akaraiwe, Nkiru; Teekhasaenee, Chaiwat; Suwan, Yanin; Supakontanasan, Wasu; Okeke, Suhanya; Uche, Nkechi; Asimadu, Ifeoma; Ayub, Humaira; Akhtar, Farah; Kosior-Jarecka, Ewa; Lukasik, Urszula; Lischinsky, Ignacio; Castro, Vania; Perez-Grossmann, Rodolfo; Sunaric Megevand, Gordana; Roy, Sylvain; Dervan, Edward; Silke, Eoin; Rao, Aparna; Sahay, Priti; Fornero, Pablo; Cuello, Osvaldo; Sivori, Delia; Zompa, Tamara; Mills, Richard; Souzeau, Emmanuelle; Mitchell, Paul; Wang, Jie Jin; Hewitt, Alex; Coote, Michael; Crowston, Jonathan; Astakhov, Sergei; Akopov, Evgeny; Emelyanov, Anton; Vysochinskaya, Vera; Kazakbaeva, Gyulli; Fayzrakhmanov, Rinat; Al-Obeidan, Saleh; Owaidhah, Ohoud; Aljasim, Leyla; Chowbay, Balram; Foo, Jia-Nee; Soh, Raphael; Sim, Kar-Seng; Xie, Zhicheng; Cheong, Augustine; Mok, Shi; Soo, Hui; Chen, Xiao; Peh, Su Qin; Heng, Khai; Husain, Rahat; Ho, Su-Ling; Hillmer, Axel; Cheng, Ching-Yu; Escudero-Domínguez, Francisco; González-Sarmiento, Rogelio; Martinon-Torres, Frederico; Salas, Antonio; Pathanapitoon, Kessara; Hansapinyo, Linda; Wanichwecharugruang, Boonsong; Kitnarong, Naris; Sakuntabhai, Anavaj; Nguyn, Hip; Nguyn, Giang; Nguyn, Trinh; Zenz, Werner; Binder, Alexander; Klobassa, Daniela; Hibberd, Martin; Davila, S.; Herms, Stefan; Nothen, Markus; Moebus, Susanne; Rautenbach, Robyn; Ziskind, Ari; Carmichael, Trevor; Ramsay, Michele; Alvarez, Lydia; Garcia, Montserrat; González-Iglesias, Hector; Rodríguez-Calvo, Pedro; Fernández-Vega Cueto, Luis; Oguz, Cilingir; Tamcelik, Nevbahar; Atalay, Eray; Batu, Bilge; Aktas, Dilek; Kasim, Burcu; Wilson, Roy; Coleman, Anne; Liu, Yutao; Challa, Pratap; Herndon, Leon; Kuchtey, Rachel; Kuchtey, John; Curtin, Karen; Chaya, Craig; Crandall, Alan; Zangwill, Linda; Wong, Tien; Nakano, Masakazu; Kinoshita, Shigeru; den Hollander, Anneke; Vesti, Eija; Fingert, John; Lee, Richard; Sit, Arthur; Shingleton, Bradford; Wang, Ningli; Cusi, Daniele; Qamar, Raheel; Kraft, Peter; Pericak-Vance, Margaret; Raychaudhuri, S; Heegaard, Steffen; Kivela, Tero; Reis, Andre; Kruse, Friedrich; Weinreb, Robert; Pasquale, Louis; Haines, Jonathan; Thorsteinsdottir, Unnur; Jonasson, Fridbert; Allingham, R; Milea, Dan; Ritch, Robert; Kubota, Toshiaki; Tashiro, Kei; Vithana, Eranga; Michael, Shazia; Topouzis, Fotis; Craig, Jamie; Dubina, Michael; Sundaresan, Periasamy; Stefansson, K; Wiggs, Janey; Pasutto, Francesca; Khor, Chiea-Chuen.
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
AU - Thorleifsson, G
AU - Mizoguchi, Takanori
AU - Igo, Robert
AU - Haripriya, Aravind
AU - Williams, Susan
AU - Astakhov, Yury
AU - Orr, Andrew
AU - Burdon, Kathryn
AU - Nakano, Satoko
AU - Mori, Kazuhiko
AU - Abu-Amero, Khalid
AU - Hauser, Michael
AU - Li, Zheng
AU - Prakadeeswari, Gopalakrishnan
AU - Bailey, Jessica
AU - Cherecheanu, Alina
AU - Kang, Jae
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, Fabian
AU - Lamari, Hasnaa
AU - Nilgun, Yildirim
AU - Bikbov, Mukharram
AU - Park, Ki-Ho
AU - Cha, Soon
AU - Yamashiro, Kenji
AU - Zenteno, Juan
AU - Jonas, Jost
AU - Kumar, Rajesh
AU - Perera, Shamira
AU - Chan, Anita
AU - Kobakhidze, Nino
AU - George, Ronnie
AU - Vijaya, Lingam
AU - Do, Tan
AU - Edward, Deepak
AU - de Juan Marcos, Lourdes
AU - Pakravan, Mohammad
AU - Moghimi, Sasan
AU - Ideta, Ryuichi
AU - Bach-Holme, Daniella
AU - Kappelgaard, Per
AU - Wirostko, Barbara
AU - Thomas, Samual
AU - Gaston, Daniel
AU - Bedard, Karen
AU - Greer, Wenda
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, Yaxing
AU - Xu, Liang
AU - Leruez, Stephanie
AU - Reynier, Pascal
AU - Chichua, George
AU - Tabagari, Sergo
AU - Uebe, Steffen
AU - Zenkel, Matthias
AU - Berner, Daniel
AU - Mossbock, Georg
AU - Weisschuh, Nicole
AU - Hoja, Ursula
AU - Welge-Luessen, Ulrich-Christoph
AU - Mardin, Christian
AU - Founti, Panayiota
AU - Chatzikyriakidou, Anthoula
AU - Pappas, Theofanis
AU - Anastasopoulos, Eleftherios
AU - Lambropoulos, Alexandros
AU - Ghosh, Arkasubhra
AU - Shetty, Rohit
AU - Porporato, Natalia
AU - Saravanan, Vijayan
AU - Venkatesh, Rangaraj
AU - Shivkumar, Chandrashekaran
AU - Kalpana, Narendran
AU - Sarangapani, Sripriya
AU - Kanavi, Mozhgan
AU - Beni, Afsaneh
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, K
AU - Higashide, Tomomi
AU - Chihara, Etsuo
AU - Ishiko, Satoshi
AU - Yoshida, Akitoshi
AU - Kiuchi, Yoshiaki
AU - Yanagi, Masahide
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
AU - Sagong, Min
AU - Park, Kyu
AU - Ahn, Jeeyun
AU - Cruz-Aguilar, Marisa
AU - Ezzouhairi, Sidi
AU - Rafei, Abderrahman
AU - Chong, Yaan
AU - Ng, Xiao
AU - Goh, Shuang
AU - Chen, Yueming
AU - Yong, Victor
AU - Khan, Muhammad
AU - Olawoye, Olusola
AU - Ashaye, Adeyinka
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
AU - Asimadu, Ifeoma
AU - Ayub, Humaira
AU - Akhtar, Farah
AU - Kosior-Jarecka, Ewa
AU - Lukasik, Urszula
AU - Lischinsky, Ignacio
AU - Castro, Vania
AU - Perez-Grossmann, Rodolfo
AU - Sunaric Megevand, Gordana
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
AU - Souzeau, Emmanuelle
AU - Mitchell, Paul
AU - Wang, Jie Jin
AU - Hewitt, Alex
AU - Coote, Michael
AU - Crowston, Jonathan
AU - Astakhov, Sergei
AU - Akopov, Evgeny
AU - Emelyanov, Anton
AU - Vysochinskaya, Vera
AU - Kazakbaeva, Gyulli
AU - Fayzrakhmanov, Rinat
AU - Al-Obeidan, Saleh
AU - Owaidhah, Ohoud
AU - Aljasim, Leyla
AU - Chowbay, Balram
AU - Foo, Jia-Nee
AU - Soh, Raphael
AU - Sim, Kar-Seng
AU - Xie, Zhicheng
AU - Cheong, Augustine
AU - Mok, Shi
AU - Soo, Hui
AU - Chen, Xiao
AU - Peh, Su Qin
AU - Heng, Khai
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
AU - Sakuntabhai, Anavaj
AU - Nguyn, Hip
AU - Nguyn, Giang
AU - Nguyn, Trinh
AU - Zenz, Werner
AU - Binder, Alexander
AU - Klobassa, Daniela
AU - Hibberd, Martin
AU - Davila, S.
AU - Herms, Stefan
AU - Nothen, Markus
AU - Moebus, Susanne
AU - Rautenbach, Robyn
AU - Ziskind, Ari
AU - Carmichael, Trevor
AU - Ramsay, Michele
AU - Alvarez, Lydia
AU - Garcia, Montserrat
AU - González-Iglesias, Hector
AU - Rodríguez-Calvo, Pedro
AU - Fernández-Vega Cueto, Luis
AU - Oguz, Cilingir
AU - Tamcelik, Nevbahar
AU - Atalay, Eray
AU - Batu, Bilge
AU - Aktas, Dilek
AU - Kasim, Burcu
AU - Wilson, Roy
AU - Coleman, Anne
AU - Liu, Yutao
AU - Challa, Pratap
AU - Herndon, Leon
AU - Kuchtey, Rachel
AU - Kuchtey, John
AU - Curtin, Karen
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
VL - 49
SP - 993
EP - 1004
JO - Nature Genetics
JF - Nature Genetics
SN - 1061-4036
IS - 7
ER -