Genetic association study of exfoliation syndrome identifies a protective rare variant at LOXL1 and five new susceptibility loci.
; Schlötzer-Schrehardt, U; Thorleifsson, G; Mizoguchi, T; Igo, RP; Haripriya, A; Williams, SE; Astakhov, YS; +279 more...Orr, AC; Burdon, KP; Nakano, S; Mori, K; Abu-Amero, K; Hauser, M; Li, Z; Prakadeeswari, G; Bailey, JNC; Cherecheanu, AP; Kang, JH; Nelson, S; Hayashi, K; Manabe, S; Kazama, S; Zarnowski, T; Inoue, K; Irkec, M; Coca-Prados, M; Sugiyama, K; Järvelä, I; Schlottmann, P; Lerner, SF; Lamari, H; Nilgün, Y; Bikbov, M; Park, KH; Cha, SC; Yamashiro, K; Zenteno, JC; Jonas, JB; Kumar, RS; Perera, SA; Chan, AS; Kobakhidze, N; George, R; Vijaya, L; Do, T; Edward, DP; de Juan Marcos, L; Pakravan, M; Moghimi, S; Ideta, R; Bach-Holm, D; Kappelgaard, P; Wirostko, B; Thomas, S; Gaston, D; Bedard, K; Greer, WL; Yang, Z; Chen, X; Huang, L; Sang, J; Jia, H; Jia, L; Qiao, C; Zhang, H; Liu, X; Zhao, B; Wang, Y; Xu, L; Leruez, S; Reynier, P; Chichua, G; Tabagari, S; Uebe, S; Zenkel, M; Berner, D; Mossböck, G; Weisschuh, N; Hoja, U; Welge-Luessen, U; Mardin, C; Founti, P; Chatzikyriakidou, A; Pappas, T; Anastasopoulos, E; Lambropoulos, A; Ghosh, A; Shetty, R; Porporato, N; Saravanan, V; Venkatesh, R; Shivkumar, C; Kalpana, N; Sarangapani, S; Kanavi, MR; Beni, AN; Yazdani, S; Lashay, A; Naderifar, H; Khatibi, N; Fea, A; Lavia, C; Dallorto, L; Rolle, T; Frezzotti, P; Paoli, D; Salvi, E; Manunta, P; Mori, Y; Miyata, K; Higashide, T; Chihara, E; Ishiko, S; Yoshida, A; Yanagi, M; Kiuchi, Y; Ohashi, T; Sakurai, T; Sugimoto, T; Chuman, H; Aihara, M; Inatani, M; Miyake, M; Gotoh, N; Matsuda, F; Yoshimura, N; Ikeda, Y; Ueno, M; Sotozono, C; Jeoung, JW; Sagong, M; Park, KH; Ahn, J; Cruz-Aguilar, M; Ezzouhairi, SM; Rafei, A; Chong, YF; Ng, XY; Goh, SR; Chen, Y; Yong, VH; Khan, MI; Olawoye, OO; Ashaye, AO; Ugbede, I; Onakoya, A; Kizor-Akaraiwe, N; Teekhasaenee, C; Suwan, Y; Supakontanasan, W; Okeke, S; Uche, NJ; Asimadu, I; Ayub, H; Akhtar, F; Kosior-Jarecka, E; Lukasik, U; Lischinsky, I; Castro, V; Grossmann, RP; Sunaric Megevand, G; Roy, S; Dervan, E; Silke, E; Rao, A; Sahay, P; Fornero, P; Cuello, O; Sivori, D; Zompa, T; Mills, RA; Souzeau, E; Mitchell, P; Wang, JJ; Hewitt, AW; Coote, M; Crowston, JG; Astakhov, SY; Akopov, EL; Emelyanov, A; Vysochinskaya, V; Kazakbaeva, G; Fayzrakhmanov, R; Al-Obeidan, SA; Owaidhah, O; Aljasim, LA; Chowbay, B; Foo, JN; Soh, RQ; Sim, KS; Xie, Z; Cheong, AW; Mok, SQ; Soo, HM; Chen, XY; Peh, SQ; Heng, KK; Husain, R; Ho, S; Hillmer, AM; Cheng, C; Escudero-Domínguez, FA; González-Sarmiento, R; Martinon-Torres, F; Salas, A; Pathanapitoon, K; Hansapinyo, L; Wanichwecharugruang, B; Kitnarong, N; Sakuntabhai, A; Nguyn, HX; Nguyn, GT; Nguyn, TV; Zenz, W; Binder, A; Klobassa, DS; Hibberd, ML; Davila, S; Herms, S; Nöthen, MM; Moebus, S; Rautenbach, RM; Ziskind, A; Carmichael, TR; Ramsay, M; Álvarez, L; García, M; González-Iglesias, H; Rodríguez-Calvo, PP; Fernández-Vega Cueto, L; Oguz, Ç; Tamcelik, N; Atalay, E; Batu, B; Aktas, D; Kasım, B; Wilson, MR; Coleman, AL; Liu, Y; Challa, P; Herndon, L; Kuchtey, RW; Kuchtey, J; Curtin, K; Chaya, CJ; Crandall, A; Zangwill, LM; Wong, TY; Nakano, M; Kinoshita, S; den Hollander, AI; Vesti, E; Fingert, JH; Lee, RK; Sit, AJ; Shingleton, BJ; Wang, N; Cusi, D; Qamar, R; Kraft, P; Pericak-Vance, MA; Raychaudhuri, S; Heegaard, S; Kivelä, T; Reis, A; Kruse, FE; Weinreb, RN; Pasquale, LR; Haines, JL; Thorsteinsdottir, U; Jonasson, F; Allingham, RR; Milea, D; Ritch, R; Kubota, T; Tashiro, K; Vithana, EN; Micheal, S; Topouzis, F; Craig, JE; Dubina, M; Sundaresan, P; Stefansson, K; Wiggs, JL; Pasutto, F; Khor, CC and
(2017)
Genetic association study of exfoliation syndrome identifies a protective rare variant at LOXL1 and five new susceptibility loci.
Nature genetics, 49 (7).
pp. 993-1004.
ISSN 1061-4036
DOI: 10.1038/ng.3875
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.