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

T Aung, M Ozaki, MC Lee, U Schlötzer-Schrehardt, G Thorleifsson, T Mizoguchi, Jr Igo RP, A Haripriya, SE Williams, YS Astakhov, AC Orr, KP Burdon, S Nakano, K Mori, K Abu-Amero, M Hauser, Z Li, G Prakadeeswari, JNC Bailey, AP CherecheanuJH Kang, S Nelson, K Hayashi, SI Manabe, S Kazama, T Zarnowski, K Inoue, M Irkec, M Coca-Prados, K Sugiyama, I Järvelä, P Schlottmann, SF Lerner, H Lamari, Y Nilgün, M Bikbov, KH Park, SC Cha, K Yamashiro, JC Zenteno, JB Jonas, RS Kumar, SA Perera, ASY Chan, N Kobakhidze, R George, L Vijaya, T Do, DP Edward, L de Juan Marcos, M Pakravan, S Moghimi, R Ideta, D Bach-Holm, P Kappelgaard, B Wirostko, S Thomas, D Gaston, K Bedard, WL Greer, Z Yang, X Chen, L Huang, J Sang, H Jia, L Jia, C Qiao, H Zhang, X Liu, B Zhao, YX Wang, L Xu, S Leruez, P Reynier, G Chichua, S Tabagari, S Uebe, M Zenkel, D Berner, G Mossböck, N Weisschuh, U Hoja, UC Welge-Luessen, C Mardin, P Founti, A Chatzikyriakidou, T Pappas, E Anastasopoulos, A Lambropoulos, A Ghosh, R Shetty, N Porporato, V Saravanan, R Venkatesh, C Shivkumar, N Kalpana, S Sarangapani, MR Kanavi, AN Beni, S Yazdani, A Lashay, H Naderifar, N Khatibi, A Fea, C Lavia, L Dallorto, T Rolle, P Frezzotti, D Paoli, E Salvi, P Manunta, Y Mori, K Miyata, T Higashide, E Chihara, S Ishiko, A Yoshida, M Yanagi, Y Kiuchi, T Ohashi, T Sakurai, T Sugimoto, H Chuman, M Aihara, M Inatani, M Miyake, N Gotoh, F Matsuda, N Yoshimura, Y Ikeda, M Ueno, C Sotozono, JW Jeoung, M Sagong, J Ahn, M Cruz-Aguilar, SM Ezzouhairi, A Rafei, YF Chong, XY Ng, SR Goh, Y Chen, VHK Yong, MI Khan, OO Olawoye, AO Ashaye, I Ugbede, A Onakoya, N Kizor-Akaraiwe, C Teekhasaenee, Y Suwan, W Supakontanasan, S Okeke, NJ Uche, I Asimadu, H Ayub, F Akhtar, E Kosior-Jarecka, U Lukasik, I Lischinsky, V Castro, RP Grossmann, GS Megevand, S Roy, E Dervan, E Silke, A Rao, P Sahay, P Fornero, O Cuello, D Sivori, T Zompa, RA Mills, E Souzeau, P Mitchell, JJ Wang, AW Hewitt, M Coote, JG Crowston, SY Astakhov, EL Akopov, A Emelyanov, V Vysochinskaya, G Kazakbaeva, R Fayzrakhmanov, SA Al-Obeidan, O Owaidhah, LA Aljasim, B Chowbay, JN Foo, RQ Soh, KS Sim, Z Xie, AWO Cheong, SQ Mok, HM Soo, XY Chen, SQ Peh, KK Heng, R Husain, SL Ho, AM Hillmer, CY Cheng, FA Escudero-Domínguez, R González-Sarmiento, F Martinon-Torres, A Salas, K Pathanapitoon, L Hansapinyo, B Wanichwecharugruang, N Kitnarong, A Sakuntabhai, HX Nguyn, GTT Nguyn, TV Nguyn, W Zenz, A Binder, DS Klobassa, ML Hibberd, S Davila, S Herms, MM Nöthen, S Moebus, RM Rautenbach, A Ziskind, TR Carmichael, M Ramsay, L Álvarez, M García, H González-Iglesias, PP Rodríguez-Calvo, LF Cueto, Ç Oguz, N Tamcelik, E Atalay, B Batu, D Aktas, B Kasım, MR Wilson, AL Coleman, Y Liu, P Challa, L Herndon, RW Kuchtey, J Kuchtey, K Curtin, CJ Chaya, A Crandall, LM Zangwill, TY Wong, M Nakano, S Kinoshita, AI den Hollander, E Vesti, JH Fingert, RK Lee, AJ Sit, BJ Shingleton, N Wang, D Cusi, R Qamar, P Kraft, MA Pericak-Vance, S Raychaudhuri, S Heegaard, T Kivelä, A Reis, FE Kruse, RN Weinreb, LR Pasquale, JL Haines, U Thorsteinsdottir, F Jonasson, RR Allingham, D Milea, R Ritch, T Kubota, K Tashiro, EN Vithana, S Micheal, F Topouzis, JE Craig, M Dubina, P Sundaresan, K Stefansson, JL Wiggs, F Pasutto, CC Khor

Research output: Contribution to journalArticlepeer-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 × 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. © 2017 Nature America, Inc., part of Springer Nature. All rights reserved.
Original languageEnglish
Pages (from-to)993-1004
Number of pages12
JournalNature Genetics
Volume49
Issue number7
DOIs
Publication statusPublished - 2017

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