A common variant mapping to CACNA1A is associated with susceptibility to exfoliation syndrome.
Exfoliation syndrome (XFS) is the most common recognizable cause of open-angle glaucoma worldwide. To better understand the etiology of XFS, we conducted a genome-wide association study (GWAS) of 1,484 cases and 1,188 controls from Japan and followed up the most significant findings in a further 6,901 cases and 20,727 controls from 17 countries across 6 continents. We discovered a genome-wide significant association between a new locus (CACNA1A rs4926244) and increased susceptibility to XFS (odds ratio (OR) = 1.16, P = 3.36 × 10(-11)). Although we also confirmed overwhelming association at the LOXL1 locus, the key SNP marker (LOXL1 rs4886776) demonstrated allelic reversal depending on the ancestry group (Japanese: OR(A allele) = 9.87, P = 2.13 × 10(-217); non-Japanese: OR(A allele) = 0.49, P = 2.35 × 10(-31)). Our findings represent the first genetic locus outside of LOXL1 surpassing genome-wide significance for XFS and provide insight into the biology and pathogenesis of the disease.
Aung, T; Ozaki, M; Mizoguchi, T; Allingham, RR; Li, Z; Haripriya, A; Nakano, S; Uebe, S; Harder, JM; Chan, ASY; Lee, MC; Burdon, KP; Astakhov, YS; Abu-Amero, KK; Zenteno, JC; Nilgün, Y; Zarnowski, T; Pakravan, M; Safieh, LA; Jia, L; Wang, YX; Williams, S; Paoli, D; Schlottmann, PG; Huang, L; Sim, KS; Foo, JN; Nakano, M; Ikeda, Y; Kumar, RS; Ueno, M; Manabe, S-I; Hayashi, K; Kazama, S; Ideta, R; Mori, Y; Miyata, K; Sugiyama, K; Higashide, T; Chihara, E; Inoue, K; Ishiko, S; Yoshida, A; Yanagi, M; Kiuchi, Y; Aihara, M; Ohashi, T; Sakurai, T; Sugimoto, T; Chuman, H; Matsuda, F; Yamashiro, K; Gotoh, N; Miyake, M; Astakhov, SY; Osman, EA; Al-Obeidan, SA; Owaidhah, O; Al-Jasim, L; Al Shahwan, S; Fogarty, RA; Leo, P; Yetkin, Y; Oğuz, Ç; Kanavi, MR; Beni, AN; Yazdani, S; Akopov, EL; Toh, K-Y; Howell, GR; Orr, AC; Goh, Y; Meah, WY; Peh, SQ; Kosior-Jarecka, E; Lukasik, U; Krumbiegel, M; Vithana, EN; Wong, TY; Liu, Y; Koch, AEA; Challa, P; Rautenbach, RM; Mackey, DA; Hewitt, AW; Mitchell, P; Wang, JJ; Ziskind, A; Carmichael, T; Ramakrishnan, R; Narendran, K; Venkatesh, R; Vijayan, S; Zhao, P; Chen, X; Guadarrama-Vallejo, D; Cheng, CY; Perera, SA; Husain, R; Ho, S-L; Welge-Luessen, U-C; Mardin, C; Schloetzer-Schrehardt, U; Hillmer, AM; Herms, S; Moebus, S; Nöthen, MM; Weisschuh, N; Shetty, R; Ghosh, A; Teo, YY; Brown, MA; Lischinsky, I; Blue Mountains Eye Study GWAS Team, ; Wellcome Trust Case Control Consortium 2, ; Crowston, JG; Coote, M; Zhao, B; Sang, J; Zhang, N; You, Q; Vysochinskaya, V; Founti, P; Chatzikyriakidou, A; Lambropoulos, A; Anastasopoulos, E; Coleman, AL; Wilson, MR; Rhee, DJ; Kang, JH; May-Bolchakova, I; Heegaard, S; Mori, K; Alward, WLM; Jonas, JB; Xu, L; Liebmann, JM; Chowbay, B; Schaeffeler, E; Schwab, M; Lerner, F; Wang, N; Yang, Z; Frezzotti, P; Kinoshita, S; Fingert, JH; Inatani, M; Tashiro, K; Reis, A; Edward, DP; Pasquale, LR; Kubota, T; Wiggs, JL; Pasutto, F; Topouzis, F; Dubina, M; Craig, JE; Yoshimura, N; Sundaresan, P; John, SWM; Ritch, R; Hauser, MA; Khor, C-C
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