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 journalArticle

26 Citations (Scopus)

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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Exfoliation Syndrome
Genetic Association Studies
Genome-Wide Association Study
Blindness
Glaucoma
Alleles
Odds Ratio
Genome
Pathology
Population
Genes

Cite this

Aung, T., Ozaki, M., Lee, MC., Schlötzer-Schrehardt, U., Thorleifsson, G., Mizoguchi, T., ... Khor, CC. (2017). Genetic association study of exfoliation syndrome identifies a protective rare variant at LOXL1 and five new susceptibility loci. Nature Genetics, 49(7), 993-1004. https://doi.org/10.1038/ng.3875

Genetic association study of exfoliation syndrome identifies a protective rare variant at LOXL1 and five new susceptibility loci. / Aung, T; Ozaki, M; Lee, MC; Schlötzer-Schrehardt, U; Thorleifsson, G; Mizoguchi, T; Igo RP, Jr; Haripriya, A; Williams, SE; Astakhov, YS; 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, SI; 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, ASY; 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, YX; Xu, L; Leruez, S; Reynier, P; Chichua, G; Tabagari, S; Uebe, S; Zenkel, M; Berner, D; Mossböck, G; Weisschuh, N; Hoja, U; Welge-Luessen, UC; 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; Ahn, J; Cruz-Aguilar, M; Ezzouhairi, SM; Rafei, A; Chong, YF; Ng, XY; Goh, SR; Chen, Y; Yong, VHK; 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; Megevand, GS; 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, AWO; Mok, SQ; Soo, HM; Chen, XY; Peh, SQ; Heng, KK; Husain, R; Ho, SL; Hillmer, AM; Cheng, CY; Escudero-Domínguez, FA; González-Sarmiento, R; Martinon-Torres, F; Salas, A; Pathanapitoon, K; Hansapinyo, L; Wanichwecharugruang, B; Kitnarong, N; Sakuntabhai, A; Nguyn, HX; Nguyn, GTT; 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; Cueto, LF; 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.

In: Nature Genetics, Vol. 49, No. 7, 2017, p. 993-1004.

Research output: Contribution to journalArticle

Aung, T, Ozaki, M, Lee, MC, Schlötzer-Schrehardt, U, Thorleifsson, G, Mizoguchi, T, Igo RP, J, Haripriya, A, Williams, SE, Astakhov, YS, 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, SI, 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, ASY, 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, YX, Xu, L, Leruez, S, Reynier, P, Chichua, G, Tabagari, S, Uebe, S, Zenkel, M, Berner, D, Mossböck, G, Weisschuh, N, Hoja, U, Welge-Luessen, UC, 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, Ahn, J, Cruz-Aguilar, M, Ezzouhairi, SM, Rafei, A, Chong, YF, Ng, XY, Goh, SR, Chen, Y, Yong, VHK, 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, Megevand, GS, 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, AWO, Mok, SQ, Soo, HM, Chen, XY, Peh, SQ, Heng, KK, Husain, R, Ho, SL, Hillmer, AM, Cheng, CY, Escudero-Domínguez, FA, González-Sarmiento, R, Martinon-Torres, F, Salas, A, Pathanapitoon, K, Hansapinyo, L, Wanichwecharugruang, B, Kitnarong, N, Sakuntabhai, A, Nguyn, HX, Nguyn, GTT, 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, Cueto, LF, 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 2017, 'Genetic association study of exfoliation syndrome identifies a protective rare variant at LOXL1 and five new susceptibility loci', Nature Genetics, vol. 49, no. 7, pp. 993-1004. https://doi.org/10.1038/ng.3875
Aung, T ; Ozaki, M ; Lee, MC ; Schlötzer-Schrehardt, U ; Thorleifsson, G ; Mizoguchi, T ; Igo RP, Jr ; Haripriya, A ; Williams, SE ; Astakhov, YS ; 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, SI ; 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, ASY ; 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, YX ; Xu, L ; Leruez, S ; Reynier, P ; Chichua, G ; Tabagari, S ; Uebe, S ; Zenkel, M ; Berner, D ; Mossböck, G ; Weisschuh, N ; Hoja, U ; Welge-Luessen, UC ; 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 ; Ahn, J ; Cruz-Aguilar, M ; Ezzouhairi, SM ; Rafei, A ; Chong, YF ; Ng, XY ; Goh, SR ; Chen, Y ; Yong, VHK ; 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 ; Megevand, GS ; 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, AWO ; Mok, SQ ; Soo, HM ; Chen, XY ; Peh, SQ ; Heng, KK ; Husain, R ; Ho, SL ; Hillmer, AM ; Cheng, CY ; Escudero-Domínguez, FA ; González-Sarmiento, R ; Martinon-Torres, F ; Salas, A ; Pathanapitoon, K ; Hansapinyo, L ; Wanichwecharugruang, B ; Kitnarong, N ; Sakuntabhai, A ; Nguyn, HX ; Nguyn, GTT ; 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 ; Cueto, LF ; 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. / Genetic association study of exfoliation syndrome identifies a protective rare variant at LOXL1 and five new susceptibility loci. In: Nature Genetics. 2017 ; Vol. 49, No. 7. pp. 993-1004.
@article{b9900f7fb7c642b4b0d3da390024180b,
title = "Genetic association study of exfoliation syndrome identifies a protective rare variant at LOXL1 and five new susceptibility loci",
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. {\circledC} 2017 Nature America, Inc., part of Springer Nature. All rights reserved.",
author = "T Aung and M Ozaki and MC Lee and U Schl{\"o}tzer-Schrehardt and G Thorleifsson and T Mizoguchi and {Igo RP}, Jr and A Haripriya and SE Williams and YS Astakhov and AC Orr and KP Burdon and S Nakano and K Mori and K Abu-Amero and M Hauser and Z Li and G Prakadeeswari and JNC Bailey and AP Cherecheanu and JH Kang and S Nelson and K Hayashi and SI Manabe and S Kazama and T Zarnowski and K Inoue and M Irkec and M Coca-Prados and K Sugiyama and I J{\"a}rvel{\"a} and P Schlottmann and SF Lerner and H Lamari and Y Nilg{\"u}n and M Bikbov and KH Park and SC Cha and K Yamashiro and JC Zenteno and JB Jonas and RS Kumar and SA Perera and ASY Chan and N Kobakhidze and R George and L Vijaya and T Do and DP Edward and {de Juan Marcos}, L and M Pakravan and S Moghimi and R Ideta and D Bach-Holm and P Kappelgaard and B Wirostko and S Thomas and D Gaston and K Bedard and WL Greer and Z Yang and X Chen and L Huang and J Sang and H Jia and L Jia and C Qiao and H Zhang and X Liu and B Zhao and YX Wang and L Xu and S Leruez and P Reynier and G Chichua and S Tabagari and S Uebe and M Zenkel and D Berner and G Mossb{\"o}ck and N Weisschuh and U Hoja and UC Welge-Luessen and C Mardin and P Founti and A Chatzikyriakidou and T Pappas and E Anastasopoulos and A Lambropoulos and A Ghosh and R Shetty and N Porporato and V Saravanan and R Venkatesh and C Shivkumar and N Kalpana and S Sarangapani and MR Kanavi and AN Beni and S Yazdani and A Lashay and H Naderifar and N Khatibi and A Fea and C Lavia and L Dallorto and T Rolle and P Frezzotti and D Paoli and E Salvi and P Manunta and Y Mori and K Miyata and T Higashide and E Chihara and S Ishiko and A Yoshida and M Yanagi and Y Kiuchi and T Ohashi and T Sakurai and T Sugimoto and H Chuman and M Aihara and M Inatani and M Miyake and N Gotoh and F Matsuda and N Yoshimura and Y Ikeda and M Ueno and C Sotozono and JW Jeoung and M Sagong and J Ahn and M Cruz-Aguilar and SM Ezzouhairi and A Rafei and YF Chong and XY Ng and SR Goh and Y Chen and VHK Yong and MI Khan and OO Olawoye and AO Ashaye and I Ugbede and A Onakoya and N Kizor-Akaraiwe and C Teekhasaenee and Y Suwan and W Supakontanasan and S Okeke and NJ Uche and I Asimadu and H Ayub and F Akhtar and E Kosior-Jarecka and U Lukasik and I Lischinsky and V Castro and RP Grossmann and GS Megevand and S Roy and E Dervan and E Silke and A Rao and P Sahay and P Fornero and O Cuello and D Sivori and T Zompa and RA Mills and E Souzeau and P Mitchell and JJ Wang and AW Hewitt and M Coote and JG Crowston and SY Astakhov and EL Akopov and A Emelyanov and V Vysochinskaya and G Kazakbaeva and R Fayzrakhmanov and SA Al-Obeidan and O Owaidhah and LA Aljasim and B Chowbay and JN Foo and RQ Soh and KS Sim and Z Xie and AWO Cheong and SQ Mok and HM Soo and XY Chen and SQ Peh and KK Heng and R Husain and SL Ho and AM Hillmer and CY Cheng and FA Escudero-Dom{\'i}nguez and R Gonz{\'a}lez-Sarmiento and F Martinon-Torres and A Salas and K Pathanapitoon and L Hansapinyo and B Wanichwecharugruang and N Kitnarong and A Sakuntabhai and HX Nguyn and GTT Nguyn and TV Nguyn and W Zenz and A Binder and DS Klobassa and ML Hibberd and S Davila and S Herms and MM N{\"o}then and S Moebus and RM Rautenbach and A Ziskind and TR Carmichael and M Ramsay and L {\'A}lvarez and M Garc{\'i}a and H Gonz{\'a}lez-Iglesias and PP Rodr{\'i}guez-Calvo and LF Cueto and {\cC} Oguz and N Tamcelik and E Atalay and B Batu and D Aktas and B Kasım and MR Wilson and AL Coleman and Y Liu and P Challa and L Herndon and RW Kuchtey and J Kuchtey and K Curtin and CJ Chaya and A Crandall and LM Zangwill and TY Wong and M Nakano and S Kinoshita and {den Hollander}, AI and E Vesti and JH Fingert and RK Lee and AJ Sit and BJ Shingleton and N Wang and D Cusi and R Qamar and P Kraft and MA Pericak-Vance and S Raychaudhuri and S Heegaard and T Kivel{\"a} and A Reis and FE Kruse and RN Weinreb and LR Pasquale and JL Haines and U Thorsteinsdottir and F Jonasson and RR Allingham and D Milea and R Ritch and T Kubota and K Tashiro and EN Vithana and S Micheal and F Topouzis and JE Craig and M Dubina and P Sundaresan and K Stefansson and JL Wiggs and F Pasutto and CC Khor",
year = "2017",
doi = "10.1038/ng.3875",
language = "English",
volume = "49",
pages = "993--1004",
journal = "Nature Genetics",
issn = "1061-4036",
publisher = "Nature Publishing Group",
number = "7",

}

TY - JOUR

T1 - Genetic association study of exfoliation syndrome identifies a protective rare variant at LOXL1 and five new susceptibility loci

AU - Aung, T

AU - Ozaki, M

AU - Lee, MC

AU - Schlötzer-Schrehardt, U

AU - Thorleifsson, G

AU - Mizoguchi, T

AU - Igo RP, Jr

AU - Haripriya, A

AU - Williams, SE

AU - Astakhov, YS

AU - Orr, AC

AU - Burdon, KP

AU - Nakano, S

AU - Mori, K

AU - Abu-Amero, K

AU - Hauser, M

AU - Li, Z

AU - Prakadeeswari, G

AU - Bailey, JNC

AU - Cherecheanu, AP

AU - Kang, JH

AU - Nelson, S

AU - Hayashi, K

AU - Manabe, SI

AU - Kazama, S

AU - Zarnowski, T

AU - Inoue, K

AU - Irkec, M

AU - Coca-Prados, M

AU - Sugiyama, K

AU - Järvelä, I

AU - Schlottmann, P

AU - Lerner, SF

AU - Lamari, H

AU - Nilgün, Y

AU - Bikbov, M

AU - Park, KH

AU - Cha, SC

AU - Yamashiro, K

AU - Zenteno, JC

AU - Jonas, JB

AU - Kumar, RS

AU - Perera, SA

AU - Chan, ASY

AU - Kobakhidze, N

AU - George, R

AU - Vijaya, L

AU - Do, T

AU - Edward, DP

AU - de Juan Marcos, L

AU - Pakravan, M

AU - Moghimi, S

AU - Ideta, R

AU - Bach-Holm, D

AU - Kappelgaard, P

AU - Wirostko, B

AU - Thomas, S

AU - Gaston, D

AU - Bedard, K

AU - Greer, WL

AU - Yang, Z

AU - Chen, X

AU - Huang, L

AU - Sang, J

AU - Jia, H

AU - Jia, L

AU - Qiao, C

AU - Zhang, H

AU - Liu, X

AU - Zhao, B

AU - Wang, YX

AU - Xu, L

AU - Leruez, S

AU - Reynier, P

AU - Chichua, G

AU - Tabagari, S

AU - Uebe, S

AU - Zenkel, M

AU - Berner, D

AU - Mossböck, G

AU - Weisschuh, N

AU - Hoja, U

AU - Welge-Luessen, UC

AU - Mardin, C

AU - Founti, P

AU - Chatzikyriakidou, A

AU - Pappas, T

AU - Anastasopoulos, E

AU - Lambropoulos, A

AU - Ghosh, A

AU - Shetty, R

AU - Porporato, N

AU - Saravanan, V

AU - Venkatesh, R

AU - Shivkumar, C

AU - Kalpana, N

AU - Sarangapani, S

AU - Kanavi, MR

AU - Beni, AN

AU - Yazdani, S

AU - Lashay, A

AU - Naderifar, H

AU - Khatibi, N

AU - Fea, A

AU - Lavia, C

AU - Dallorto, L

AU - Rolle, T

AU - Frezzotti, P

AU - Paoli, D

AU - Salvi, E

AU - Manunta, P

AU - Mori, Y

AU - Miyata, K

AU - Higashide, T

AU - Chihara, E

AU - Ishiko, S

AU - Yoshida, A

AU - Yanagi, M

AU - Kiuchi, Y

AU - Ohashi, T

AU - Sakurai, T

AU - Sugimoto, T

AU - Chuman, H

AU - Aihara, M

AU - Inatani, M

AU - Miyake, M

AU - Gotoh, N

AU - Matsuda, F

AU - Yoshimura, N

AU - Ikeda, Y

AU - Ueno, M

AU - Sotozono, C

AU - Jeoung, JW

AU - Sagong, M

AU - Ahn, J

AU - Cruz-Aguilar, M

AU - Ezzouhairi, SM

AU - Rafei, A

AU - Chong, YF

AU - Ng, XY

AU - Goh, SR

AU - Chen, Y

AU - Yong, VHK

AU - Khan, MI

AU - Olawoye, OO

AU - Ashaye, AO

AU - Ugbede, I

AU - Onakoya, A

AU - Kizor-Akaraiwe, N

AU - Teekhasaenee, C

AU - Suwan, Y

AU - Supakontanasan, W

AU - Okeke, S

AU - Uche, NJ

AU - Asimadu, I

AU - Ayub, H

AU - Akhtar, F

AU - Kosior-Jarecka, E

AU - Lukasik, U

AU - Lischinsky, I

AU - Castro, V

AU - Grossmann, RP

AU - Megevand, GS

AU - Roy, S

AU - Dervan, E

AU - Silke, E

AU - Rao, A

AU - Sahay, P

AU - Fornero, P

AU - Cuello, O

AU - Sivori, D

AU - Zompa, T

AU - Mills, RA

AU - Souzeau, E

AU - Mitchell, P

AU - Wang, JJ

AU - Hewitt, AW

AU - Coote, M

AU - Crowston, JG

AU - Astakhov, SY

AU - Akopov, EL

AU - Emelyanov, A

AU - Vysochinskaya, V

AU - Kazakbaeva, G

AU - Fayzrakhmanov, R

AU - Al-Obeidan, SA

AU - Owaidhah, O

AU - Aljasim, LA

AU - Chowbay, B

AU - Foo, JN

AU - Soh, RQ

AU - Sim, KS

AU - Xie, Z

AU - Cheong, AWO

AU - Mok, SQ

AU - Soo, HM

AU - Chen, XY

AU - Peh, SQ

AU - Heng, KK

AU - Husain, R

AU - Ho, SL

AU - Hillmer, AM

AU - Cheng, CY

AU - Escudero-Domínguez, FA

AU - González-Sarmiento, R

AU - Martinon-Torres, F

AU - Salas, A

AU - Pathanapitoon, K

AU - Hansapinyo, L

AU - Wanichwecharugruang, B

AU - Kitnarong, N

AU - Sakuntabhai, A

AU - Nguyn, HX

AU - Nguyn, GTT

AU - Nguyn, TV

AU - Zenz, W

AU - Binder, A

AU - Klobassa, DS

AU - Hibberd, ML

AU - Davila, S

AU - Herms, S

AU - Nöthen, MM

AU - Moebus, S

AU - Rautenbach, RM

AU - Ziskind, A

AU - Carmichael, TR

AU - Ramsay, M

AU - Álvarez, L

AU - García, M

AU - González-Iglesias, H

AU - Rodríguez-Calvo, PP

AU - Cueto, LF

AU - Oguz, Ç

AU - Tamcelik, N

AU - Atalay, E

AU - Batu, B

AU - Aktas, D

AU - Kasım, B

AU - Wilson, MR

AU - Coleman, AL

AU - Liu, Y

AU - Challa, P

AU - Herndon, L

AU - Kuchtey, RW

AU - Kuchtey, J

AU - Curtin, K

AU - Chaya, CJ

AU - Crandall, A

AU - Zangwill, LM

AU - Wong, TY

AU - Nakano, M

AU - Kinoshita, S

AU - den Hollander, AI

AU - Vesti, E

AU - Fingert, JH

AU - Lee, RK

AU - Sit, AJ

AU - Shingleton, BJ

AU - Wang, N

AU - Cusi, D

AU - Qamar, R

AU - Kraft, P

AU - Pericak-Vance, MA

AU - Raychaudhuri, S

AU - Heegaard, S

AU - Kivelä, T

AU - Reis, A

AU - Kruse, FE

AU - Weinreb, RN

AU - Pasquale, LR

AU - Haines, JL

AU - Thorsteinsdottir, U

AU - Jonasson, F

AU - Allingham, RR

AU - Milea, D

AU - Ritch, R

AU - Kubota, T

AU - Tashiro, K

AU - Vithana, EN

AU - Micheal, S

AU - Topouzis, F

AU - Craig, JE

AU - Dubina, M

AU - Sundaresan, P

AU - Stefansson, K

AU - Wiggs, JL

AU - Pasutto, F

AU - Khor, CC

PY - 2017

Y1 - 2017

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. © 2017 Nature America, Inc., part of Springer Nature. All rights reserved.

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. © 2017 Nature America, Inc., part of Springer Nature. All rights reserved.

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 -