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

Journal name:
Nature Genetics
Volume:
49,
Pages:
993–1004
Year published:
DOI:
doi:10.1038/ng.3875
Received
Accepted
Published online

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.

At a glance

Figures

  1. LOXL1 p.Tyr407Phe regulates ECM synthesis and improves cellular adhesion.
    Figure 1: LOXL1 p.Tyr407Phe regulates ECM synthesis and improves cellular adhesion.

    (a) Schematic diagram of LOXL1 indicating the protein domain positions for the variants evaluated in this study. (b) Immunofluorescent staining of HA-tagged LOXL1 variants overexpressed in HLECs labeled with antibody to HA for detection of overexpressed forms of LOXL1 (red) and antibody to elastin (green). Cell nuclei are stained in blue. The heat map for elastin indicates the intensity of elastin staining from red (increased expression) to purple (decreased expression). (c) Immunofluorescent staining of HA-tagged LOXL1 variants overexpressed in HLECs labeled with antibody to HA for detection of overexpressed forms of LOXL1 (red) and antibody to collagen IV (green). Cell nuclei are stained in blue. The heat map for collagen IV indicates the intensity of collagen IV staining from red (increased expression) to purple (decreased expression). (d) Immunofluorescent staining of HA-tagged LOXL1 variants overexpressed in HLECs labeled with antibody to HA for detection of overexpressed forms of LOXL1 (red) and antibody to fibrillin-1 (green). Cell nuclei are stained in blue. The heat map for fibrillin-1 indicates the intensity of fibrillin-1 staining from red (increased expression) to purple (decreased expression). (e) Cumulative average of impedance values (as a surrogate for cellular adhesion strength) measured over 35 h following nucleofection of HLECs overexpressing the four tested LOXL1 haplotypes. In each plot, the middle line represents the median, the box shows the interquartile range, and the whiskers extend to the minimum and maximum values. Data are shown from four independent experiments. **P < 0.01 when compared to the rare, protective LOXL1 p.Phe407-carrying G-A-T haplotype. The four haplotypes tested were LOXL1 G-A-T, G-A-A, T-G-A and G-G-A. This experiment was further validated in Supplementary Figure 7.

  2. Manhattan plot of the results from the GWAS discovery plus replication meta-analysis comprising 13,620 XFS cases and 109,837 controls.
    Figure 2: Manhattan plot of the results from the GWAS discovery plus replication meta-analysis comprising 13,620 XFS cases and 109,837 controls.

    Genetic markers are plotted according to chromosomal location on the horizontal axis, and statistical significance is plotted on the vertical axis. SNP markers at seven independent loci surpassed genome-wide significance (defined as P ≤ 5 × 10−8). They are LOXL1, CACNA1A, POMP, TMEM136, AGPAT1, SEMA6A and RBMS3.

  3. Expression of POMP protein in ocular tissues of normal human donor eyes and donor eyes with XFS, as determined by immunoblotting and immunohistochemistry.
    Figure 3: Expression of POMP protein in ocular tissues of normal human donor eyes and donor eyes with XFS, as determined by immunoblotting and immunohistochemistry.

    (af) Immunofluorescence labeling of normal eye tissues shows punctate POMP immunopositivity (green fluorescence) in the cytoplasm of the corneal epithelium (a), the corneal endothelium (b), the limbal epithelium and stromal cells (c), the trabecular meshwork endothelium (d), the ciliary epithelium (e) and the retinal cell layers (f). (gm) Reduced POMP protein expression levels in the iris and ciliary body tissues of XFS eyes as compared to age-matched controls shown by immunoblot analysis (g) and immunofluorescence labeling of iridal (h,k) and ciliary (i,l) epithelia, as well as vascular endothelia in the iris (k,m). Reduced staining intensity in XFS tissues is associated with LOXL1-positive exfoliation material accumulations (red immunofluorescence) on the surface of the iris pigment epithelium (k), ciliary epithelium (m) and iris blood vessel walls (m). Immunoblots (cropped images) and densitometry analysis show reduced POMP protein expression in iris and ciliary body tissue lysates of XFS eyes as compared to control eyes (g). Data are shown as the POMP/β-actin ratio (n = 6 for each group; mean ± s.d.; *P < 0.01, **P < 0.005, unpaired two-sided t test); uncropped versions of all immunoblots are shown in Supplementary Figure 16. BV, blood vessel; CE, ciliary epithelium, CoE, corneal epithelium; DM, descemet membrane; GCL, retinal ganglion cell layer; INL, inner nuclear layer; IPE, iris pigment epithelium; LE, limbal epithelium; ONL, outer nuclear layer; SC, Schlemm's canal; ST, stroma; TM, trabecular meshwork. DAPI nuclear counterstaining is shown in blue. Scale bars, 100 μm in c, d and f and 20 μm in a, b, e and hm.

  4. Expression of TMEM136 protein in the ocular tissues of normal human donor eyes and donor eyes with XFS, as determined by immunoblotting and immunohistochemistry.
    Figure 4: Expression of TMEM136 protein in the ocular tissues of normal human donor eyes and donor eyes with XFS, as determined by immunoblotting and immunohistochemistry.

    (af) Immunofluorescence labeling of normal eye tissues shows cytoplasmic TMEM136 immunopositivity (green fluorescence) in limbal blood vessels (a), trabecular meshwork and Schlemm's canal endothelium (b), walls of aqueous veins (arrows) (c), blood vessels of the iris (arrows) (d), blood vessels and epithelia of the ciliary body (e) and retinal blood vessels and cell layers (f). (gk) Reduced TMEM136 protein expression levels in iris and ciliary body tissues of XFS eyes as compared to age-matched controls shown by immunoblot analysis (g) and immunofluorescence labeling of iridal (h,k) and ciliary (i,l) epithelia, as well as vascular endothelia in the iris (j,m). Reduced staining intensity in XFS tissues is associated with LOXL1-positive exfoliation material accumulations (red immunofluorescence) on the surface of the iris pigment epithelium (k), ciliary epithelium (l) and iris blood vessel walls (m). Immunoblots (cropped images) and densitometry analysis show reduced TMEM136 protein (isoform 1 at 28 KDa and isoform 3 at 31 KDa) expression in iris and ciliary body tissue lysates of XFS eyes as compared to control eyes (g). Data are shown as the TMEM136/β-actin ratio (mean ± s.d.; n = 6 for each group; *P < 0.01, **P < 0.005, unpaired two-sided t test); uncropped versions of all immunoblots are shown in Supplementary Figure 17. AV, aqueous vein; BV, blood vessel; CE, ciliary epithelium; DIL, dilator muscle; GCL, retinal ganglion cell layer; INL, inner nuclear layer; IPE, iris pigment epithelium; LE, limbal epithelium; ONL, outer nuclear layer; SC, Schlemm's canal; ST, stroma; TM, trabecular meshwork. DAPI nuclear counterstaining is in blue. Scale bars, 200 μm in a, 100 μm in bf and 20 μm in hm.

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Author information

  1. These authors contributed equally to this work.

    • Tin Aung,
    • Mineo Ozaki,
    • Mei Chin Lee,
    • Ursula Schlötzer-Schrehardt,
    • Gudmar Thorleifsson,
    • Takanori Mizoguchi,
    • Robert P Igo Jr,
    • Aravind Haripriya,
    • Susan E Williams,
    • Yury S Astakhov,
    • Andrew C Orr,
    • Kathryn P Burdon,
    • Satoko Nakano,
    • Kazuhiko Mori,
    • Khaled Abu-Amero &
    • Michael Hauser
  2. These authors jointly directed this work.

    • Fridbert Jonasson,
    • R Rand Allingham,
    • Dan Milea,
    • Robert Ritch,
    • Toshiaki Kubota,
    • Kei Tashiro,
    • Eranga N Vithana,
    • Shazia Micheal,
    • Fotis Topouzis,
    • Jamie E Craig,
    • Michael Dubina,
    • Periasamy Sundaresan,
    • Kari Stefansson,
    • Janey L Wiggs,
    • Francesca Pasutto &
    • Chiea Chuen Khor

Affiliations

  1. Singapore Eye Research Institute, Singapore.

    • Tin Aung,
    • Mei Chin Lee,
    • Michael Hauser,
    • Shamira A Perera,
    • Anita S Y Chan,
    • Yaan Fun Chong,
    • Xiao Yu Ng,
    • Shuang Ru Goh,
    • Yueming Chen,
    • Victor H K Yong,
    • Ching-Yu Cheng,
    • Eray Atalay,
    • Tien Yin Wong,
    • R Rand Allingham,
    • Dan Milea,
    • Eranga N Vithana &
    • Chiea Chuen Khor
  2. Singapore National Eye Center, Singapore.

    • Tin Aung,
    • Shamira A Perera,
    • Anita S Y Chan,
    • Rahat Husain,
    • Ching-Yu Cheng,
    • Tien Yin Wong &
    • Dan Milea
  3. Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.

    • Tin Aung,
    • Ching-Yu Cheng,
    • Tien Yin Wong &
    • Eranga N Vithana
  4. Ozaki Eye Hospital, Hyuga, Miyazaki, Japan.

    • Mineo Ozaki
  5. Department of Ophthalmology, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan.

    • Mineo Ozaki,
    • Takako Sugimoto &
    • Hideki Chuman
  6. Academic Clinical Program for Ophthalmology and Visual Sciences, Office of Clinical and Academic Faculty Affairs, Duke–NUS Graduate Medical School, Singapore.

    • Mei Chin Lee,
    • Anita S Y Chan,
    • Ching-Yu Cheng &
    • Dan Milea
  7. Department of Ophthalmology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.

    • Ursula Schlötzer-Schrehardt,
    • Matthias Zenkel,
    • Daniel Berner,
    • Ursula Hoja,
    • Ulrich-Christoph Welge-Luessen,
    • Christian Mardin &
    • Friedrich E Kruse
  8. deCODE Genetics, Reykjavik, Iceland.

    • Gudmar Thorleifsson,
    • Unnur Thorsteinsdottir &
    • Kari Stefansson
  9. Mizoguchi Eye Hospital, Sasebo, Japan.

    • Takanori Mizoguchi
  10. Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, Ohio, USA.

    • Robert P Igo Jr,
    • Jessica N Cooke Bailey &
    • Jonathan L Haines
  11. Aravind Eye Hospital, Madurai, India.

    • Aravind Haripriya
  12. Division of Ophthalmology, University of the Witwatersrand, Johannesburg, South Africa.

    • Susan E Williams &
    • Trevor R Carmichael
  13. Department of Ophthalmology, Pavlov First Saint Petersburg State Medical University, St. Petersburg, Russia.

    • Yury S Astakhov,
    • Sergei Y Astakhov,
    • Eugeny L Akopov,
    • Anton Emelyanov &
    • Michael Dubina
  14. Department of Ophthalmology, Dalhousie University, Halifax, Nova Scotia, Canada.

    • Andrew C Orr
  15. Department of Pathology, Dalhousie University, Halifax, Nova Scotia, Canada.

    • Andrew C Orr,
    • Daniel Gaston,
    • Karen Bedard &
    • Wenda L Greer
  16. Department of Ophthalmology, Flinders University, Adelaide, South Australia, Australia.

    • Kathryn P Burdon,
    • Richard A Mills,
    • Emmanuelle Souzeau &
    • Jamie E Craig
  17. Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia.

    • Kathryn P Burdon &
    • Alex W Hewitt
  18. Department of Ophthalmology, Oita University Faculty of Medicine, Oita, Japan.

    • Satoko Nakano &
    • Toshiaki Kubota
  19. Department of Ophthalmology, Kyoto Prefectural University of Medicine, Kyoto, Japan.

    • Kazuhiko Mori,
    • Yoko Ikeda,
    • Morio Ueno,
    • Chie Sotozono &
    • Shigeru Kinoshita
  20. Department of Ophthalmology, College of Medicine, King Saud University, Riyadh, Saudi Arabia.

    • Khaled Abu-Amero &
    • Saleh A Al-Obeidan
  21. Department of Ophthalmology, College of Medicine, University of Florida, Jacksonville, Florida, USA.

    • Khaled Abu-Amero
  22. Department of Ophthalmology, Duke University Eye Center, Durham, North Carolina, USA.

    • Michael Hauser,
    • Pratap Challa,
    • Leon Herndon &
    • R Rand Allingham
  23. Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA.

    • Michael Hauser
  24. Genome Institute of Singapore, Singapore.

    • Zheng Li,
    • Jia Nee Foo,
    • Raphael Q Soh,
    • Kar Seng Sim,
    • Zhicheng Xie,
    • Augustine W O Cheong,
    • Shi Qi Mok,
    • Hui Meng Soo,
    • Xiao Yin Chen,
    • Su Qin Peh,
    • Khai Koon Heng,
    • Axel M Hillmer,
    • Martin L Hibberd,
    • Sonia Davila &
    • Chiea Chuen Khor
  25. Department of Genetics, Aravind Medical Research Foundation, Madurai, India.

    • Gopalakrishnan Prakadeeswari &
    • Vijayan Saravanan
  26. 'Carol Davila' University of Medicine and Pharmacy, Bucharest, Romania.

    • Alina Popa Cherecheanu
  27. Department of Ophthalmology, University Emergency Hospital, Bucharest, Romania.

    • Alina Popa Cherecheanu
  28. Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.

    • Jae H Kang &
    • Louis R Pasquale
  29. Department of Biostatistics, University of Washington, Seattle, Washington, USA.

    • Sarah Nelson
  30. Hayashi Eye Hospital, Fukuoka, Japan.

    • Ken Hayashi &
    • Shin-ichi Manabe
  31. Shinjo Eye Clinic, Miyazaki, Japan.

    • Shigeyasu Kazama
  32. Department of Diagnostics and Microsurgery of Glaucoma, Medical University, Lublin, Poland.

    • Tomasz Zarnowski,
    • Ewa Kosior-Jarecka &
    • Urszula Lukasik
  33. Inoue Eye Hospital, Tokyo, Japan.

    • Kenji Inoue
  34. Department of Ophthalmology, Hacettepe University, Faculty of Medicine, Ankara, Turkey.

    • Murat Irkec &
    • Burcu Kasım
  35. Fernández-Vega University Institute and Foundation of Ophthalmological Research, University of Oviedo, Oviedo, Spain.

    • Miguel Coca-Prados,
    • Lydia Álvarez,
    • Montserrat García,
    • Héctor González-Iglesias,
    • Pedro P Rodríguez-Calvo &
    • Luis Fernández-Vega Cueto
  36. Fernández-Vega Ophthalmological Institute, Oviedo, Spain.

    • Miguel Coca-Prados,
    • Lydia Álvarez,
    • Montserrat García,
    • Héctor González-Iglesias,
    • Pedro P Rodríguez-Calvo &
    • Luis Fernández-Vega Cueto
  37. Department of Ophthalmology and Visual Science, Yale University School of Medicine, New Haven, Connecticut, USA.

    • Miguel Coca-Prados
  38. Department of Ophthalmology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan.

    • Kazuhisa Sugiyama &
    • Tomomi Higashide
  39. Department of Medical Genetics, University of Helsinki, Helsinki, Finland.

    • Irma Järvelä
  40. Organización Médica de Investigación, Buenos Aires, Argentina.

    • Patricio Schlottmann
  41. Fundación para el Estudio del Glaucoma, Buenos Aires, Argentina.

    • S Fabian Lerner &
    • Delia Sivori
  42. Clinique Spécialisée en Ophtalmologie Mohammedia, Mohammedia, Morocco.

    • Hasnaa Lamari &
    • Sidi M Ezzouhairi
  43. Department of Ophthalmology, Eskisehir Osmangazi University, Meselik, Eskisehir, Turkey.

    • Yildirim Nilgün
  44. Ufa Eye Research Institute, Ufa, Russia.

    • Mukharram Bikbov,
    • Gyulli Kazakbaeva &
    • Rinat Fayzrakhmanov
  45. Department of Ophthalmology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea.

    • Ki Ho Park &
    • Jin Wook Jeoung
  46. Department of Ophthalmology, Yeungnam University College of Medicine, Daegu, Republic of Korea.

    • Soon Cheol Cha &
    • Min Sagong
  47. Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Kyoto, Japan.

    • Kenji Yamashiro,
    • Masahiro Miyake &
    • Nagahisa Yoshimura
  48. Department of Ophthalmology, Otsu Red Cross Hospital, Otsu, Japan.

    • Kenji Yamashiro
  49. Genetics Department, Institute of Ophthalmology 'Conde de Valenciana', Mexico City, Mexico.

    • Juan C Zenteno &
    • Marisa Cruz-Aguilar
  50. Biochemistry Department, Faculty of Medicine, UNAM, Mexico City, Mexico.

    • Juan C Zenteno
  51. Department of Ophthalmology, Medical Faculty Mannheim of the Ruprecht Karls University of Heidelberg, Mannheim, Germany.

    • Jost B Jonas
  52. Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing Ophthalmology and Visual Science Key Laboratory, Beijing, China.

    • Jost B Jonas,
    • Jinghong Sang,
    • Hongyan Jia,
    • Liyun Jia,
    • Chunyan Qiao,
    • Hui Zhang,
    • Bowen Zhao,
    • Liang Xu &
    • Ningli Wang
  53. Narayana Nethralaya Eye Hospital, Bangalore, India.

    • Rajesh S Kumar &
    • Rohit Shetty
  54. Chichua Medical Center Mzera, LLC, Tbilisi, Georgia.

    • Nino Kobakhidze &
    • George Chichua
  55. Jadhavbhai Nathamal Singhvi Department of Glaucoma, Medical Research Foundation, Chennai, India.

    • Ronnie George &
    • Lingam Vijaya
  56. Vietnam National Institute of Ophthalmology, Hanoi, Vietnam.

    • Tan Do,
    • Hip X Nguyn,
    • Giang T T Nguyn &
    • Trình V Nguyn
  57. King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia.

    • Deepak P Edward,
    • Ohoud Owaidhah &
    • Leyla Ali Aljasim
  58. Department of Ophthalmology and Visual Sciences, Illinois Eye and Ear Infirmary, College of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA.

    • Deepak P Edward
  59. Department of Ophthalmology, University Hospital of Salamanca, Salamanca, Spain.

    • Lourdes de Juan Marcos &
    • Francisco A Escudero-Domínguez
  60. Institute for Biomedical Research of Salamanca (IBSAL), Salamanca, Spain.

    • Lourdes de Juan Marcos &
    • Rogelio González-Sarmiento
  61. Ophthalmic Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

    • Mohammad Pakravan,
    • Afsaneh Naderi Beni &
    • Shahin Yazdani
  62. Farabi Eye Hospital, Tehran University Eye Research Center, Tehran University of Medical Sciences, Tehran, Iran.

    • Sasan Moghimi,
    • Alireza lashay,
    • Homa Naderifar &
    • Nassim Khatibi
  63. Ideta Eye Hospital, Kumamoto City, Japan.

    • Ryuichi Ideta
  64. Eye Clinic, Rigshospitalet–Glostrup, Glostrup, Denmark.

    • Daniella Bach-Holm &
    • Per Kappelgaard
  65. John A. Moran Eye Center, Department of Ophthalmology, University of Utah, Salt Lake City, Utah, USA.

    • Barbara Wirostko,
    • Samuel Thomas,
    • Karen Curtin,
    • Craig J Chaya &
    • Alan Crandall
  66. Sichuan Provincial Key Laboratory for Human Disease Gene Study, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China.

    • Zhenglin Yang
  67. School of Medicine, University of Electronic Science and Technology of China, Chengdu, China.

    • Zhenglin Yang
  68. Department of Ophthalmology, First Affiliated Hospital of Xinjiang Medical University, Urumchi, China.

    • Xueyi Chen
  69. Center for Human Molecular Biology and Genetics, Institute of Laboratory Medicine, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu, China.

    • Lulin Huang
  70. Sichuan Translational Research Hospital, Chinese Academy of Sciences, Chengdu, China.

    • Lulin Huang
  71. Beijing Institute of Ophthalmology, Beijing Tongren Hospital, Capital Medical University, Beijing, China.

    • Liyun Jia,
    • Bowen Zhao,
    • Ya-Xing Wang &
    • Ningli Wang
  72. Shenzhen Key Laboratory of Ophthalmology, Shenzhen Eye Hospital, Jinan University, Shenzhen, China.

    • Xuyang Liu
  73. Département d'Ophtalmologie, Centre Hospitalier Universitaire, Angers, France.

    • Stéphanie Leruez
  74. Département de Biochimie et Génétique, Centre Hospitalier Universitaire, Angers, France.

    • Pascal Reynier
  75. David Tvildiani Medical University, Tbilisi, Georgia.

    • Sergo Tabagari &
    • André Reis
  76. Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.

    • Steffen Uebe &
    • Francesca Pasutto
  77. Department of Ophthalmology, Medical University Graz, Graz, Austria.

    • Georg Mossböck
  78. Institute for Ophthalmic Research, Centre for Ophthalmology, University of Tübingen, Tübingen, Germany.

    • Nicole Weisschuh
  79. Department of Ophthalmology, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece.

    • Panayiota Founti,
    • Theofanis Pappas,
    • Eleftherios Anastasopoulos &
    • Fotis Topouzis
  80. Laboratory of General Biology, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece.

    • Anthi Chatzikyriakidou &
    • Alexandros Lambropoulos
  81. GROW Research Laboratory, Narayana Nethralaya Foundation, Bangalore, India.

    • Arkasubhra Ghosh
  82. Santa Lucia Eye Hospital from Buenos Aires, Buenos Aires, Argentina.

    • Natalia Porporato
  83. Aravind Eye Hospital, Pondicherry, India.

    • Rengaraj Venkatesh
  84. Aravind Eye Hospital, Tirunelveli, India.

    • Chandrashekaran Shivkumar
  85. Aravind Eye Hospital, Coimbatore, India.

    • Narendran Kalpana
  86. Vision Research Foundation, Chennai, India.

    • Sripriya Sarangapani
  87. Ocular Tissue Engineering Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

    • Mozhgan R Kanavi
  88. Dipartimento di Scienze Chirurgiche, Università di Torino, Turin, Italy.

    • Antonio Fea,
    • Carlo Lavia,
    • Laura Dallorto &
    • Teresa Rolle
  89. Ophthalmology Unit, Department of Medicine, Surgery and Neuroscience, University of Siena, Siena, Italy.

    • Paolo Frezzotti
  90. Department of Ophthalmology, Monfalcone Hospital, Gorizia, Italy.

    • Daniela Paoli
  91. Department of Health Sciences, University of Milan, Milan, Italy.

    • Erika Salvi
  92. Department of Nephrology, University Vita-Salute San Raffaele, Milan, Italy.

    • Paolo Manunta
  93. Miyata Eye Hospital, Miyazaki, Japan.

    • Yosai Mori &
    • Kazunori Miyata
  94. Sensho-kai Eye Institute, Kyoto, Japan.

    • Etsuo Chihara
  95. Department of Medicine and Engineering Combined Research Institute, Asahikawa Medical University, Asahikawa, Japan.

    • Satoshi Ishiko
  96. Department of Ophthalmology, Asahikawa Medical University, Asahikawa, Japan.

    • Akitoshi Yoshida
  97. Department of Ophthalmology and Visual Sciences, Hiroshima University, Hiroshima, Japan.

    • Masahide Yanagi &
    • Yoshiaki Kiuchi
  98. Ohashi Eye Center, Sapporo, Japan.

    • Tsutomu Ohashi
  99. Tane Memorial Eye Hospital, Osaka, Japan.

    • Toshiya Sakurai
  100. Department of Ophthalmology, University of Tokyo, Tokyo, Japan.

    • Makoto Aihara
  101. Department of Ophthalmology, Faculty of Medical Science, University of Fukui, Fukui, Japan.

    • Masaru Inatani
  102. Center for Genomic Medicine, INSERM U852, Kyoto University Graduate School of Medicine, Kyoto, Japan.

    • Norimoto Gotoh &
    • Fumihiko Matsuda
  103. Tazuke Kofukai Foundation, Medical Research Institute, Kitano Hospital, Osaka, Japan.

    • Nagahisa Yoshimura
  104. Department of Ophthalmology, Seoul National University Bundang Hospital, Gyeonggi, Republic of Korea.

    • Kyu Hyung Park
  105. Department of Ophthalmology, Seoul Metropolitan Government Seoul National University Boramae Medical Center, Seoul, Republic of Korea.

    • Jeeyun Ahn
  106. Laboratoires RAFEI, Mohammedia, Morocco.

    • Abderrahman Rafei
  107. Department of Human Genetics, Radboud University Medical Centre, Nijmegen, the Netherlands.

    • Muhammad Imran Khan &
    • Anneke I den Hollander
  108. Department of Ophthalmology, College of Medicine, University of Ibadan, Ibadan, Nigeria.

    • Olusola O Olawoye &
    • Adeyinka O Ashaye
  109. Department of Ophthalmology, University College Hospital, Ibadan, Nigeria.

    • Olusola O Olawoye &
    • Adeyinka O Ashaye
  110. ECWA Eye Hospital, Kano, Nigeria.

    • Idakwo Ugbede
  111. Department of Ophthalmology, University of Lagos, Lagos, Nigeria.

    • Adeola Onakoya
  112. Guinness Eye Centre, Lagos University Teaching Hospital, Lagos, Nigeria.

    • Adeola Onakoya
  113. Department of Ophthalmology, ESUT Teaching Hospital Parklane, Enugu, Nigeria.

    • Nkiru Kizor-Akaraiwe,
    • Suhanya Okeke &
    • Ifeoma Asimadu
  114. Eye Specialists Hospital, Enugu, Nigeria.

    • Nkiru Kizor-Akaraiwe,
    • Suhanya Okeke &
    • Nkechi J Uche
  115. Department of Ophthalmology, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.

    • Chaiwat Teekhasaenee,
    • Yanin Suwan &
    • Wasu Supakontanasan
  116. Department of Ophthalmology, University of Nigeria Teaching Hospital, Ituku-Ozalla, Enugu, Nigeria.

    • Nkechi J Uche
  117. Department of Ophthalmology, College of Medicine, University of Nigeria, Nsukka, Ituku Ozalla Campus, Enugu, Nigeria.

    • Nkechi J Uche
  118. Department of Environmental Sciences, COMSATS Institute of Information Technology, Abbottabad, Pakistan.

    • Humaira Ayub
  119. Pakistan Institute of Ophthalmology, Al-Shifa Trust Eye Hospital, Rawalpindi, Pakistan.

    • Farah Akhtar
  120. Centro Oftalmologico Lischinsky, Tucumán, Argentina.

    • Ignacio Lischinsky
  121. Universidad Peruana Cayetano Heredia, Hospital Nacional Arzobispo Loayza, Lima, Peru.

    • Vania Castro
  122. Instituto de Glaucoma y Catarata, Lima, Peru.

    • Rodolfo Perez Grossmann
  123. Clinical Research Centre Adolphe de Rothschild, Société Médicale de Beaulieu, Geneva, Switzerland.

    • Gordana Sunaric Megevand &
    • Sylvain Roy
  124. Mater Misericordiae University Hospital, Dublin, Ireland.

    • Edward Dervan &
    • Eoin Silke
  125. Shri Mithu Tulsi, LV Prasad Eye Institute, Bhubaneswar, India.

    • Aparna Rao &
    • Priti Sahay
  126. Hospital Córdoba, Córdoba, Argentina.

    • Pablo Fornero &
    • Osvaldo Cuello
  127. Centro Oftalmologico Charles, Buenos Aires, Argentina.

    • Tamara Zompa
  128. Centre for Vision Research, Department of Ophthalmology and Westmead Institute for Medical Research, University of Sydney, Sydney, New South Wales, Australia.

    • Paul Mitchell &
    • Jie Jin Wang
  129. Centre for Eye Research Australia (CERA), University of Melbourne, Royal Victorian Eye and Ear Hospital, Melbourne, Victoria, Australia.

    • Alex W Hewitt,
    • Michael Coote &
    • Jonathan G Crowston
  130. St. Petersburg Academic University, St. Petersburg, Russia.

    • Anton Emelyanov,
    • Vera Vysochinskaya &
    • Michael Dubina
  131. Clinical Pharmacology, SingHealth, Singapore.

    • Balram Chowbay
  132. Clinical Pharmacology Laboratory, National Cancer Centre, Singapore.

    • Balram Chowbay
  133. Office of Clinical Sciences, Duke–NUS Medical School, Singapore.

    • Balram Chowbay
  134. Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore.

    • Jia Nee Foo
  135. Department of Ophthalmology, Tan Tock Seng Hospital, Singapore.

    • Su-Ling Ho
  136. Molecular Medicine Unit, Department of Medicine, University of Salamanca, Salamanca, Spain.

    • Rogelio González-Sarmiento
  137. Translational Pediatrics and Infectious Diseases, Hospital Clínico Universitario de Santiago, Santiago de Compostela, Spain.

    • Frederico Martinon-Torres
  138. GENVIP Research Group, Instituto de Investigación Sanitaria de Santiago, Santiago de Compostela, Spain.

    • Frederico Martinon-Torres
  139. Unidade de Xenética, Departamento de Anatomía Patolóxica e Ciencias Forenses, Instituto de Ciencias Forenses, Facultade de Medicina, Universidade de Santiago de Compostela, Santiago de Compostela, Spain.

    • Antonio Salas
  140. Instituto de Ciencias Forenses, Facultade de Medicina, Universidade de Santiago de Compostela, Santiago de Compostela, Spain.

    • Antonio Salas
  141. Department of Ophthalmology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.

    • Kessara Pathanapitoon &
    • Linda Hansapinyo
  142. Department of Ophthalmology, Rajavithi Hospital, Bangkok, Thailand.

    • Boonsong Wanichwecharugruang
  143. Department of Ophthalmology, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand.

    • Naris Kitnarong
  144. Institut Pasteur, Functional Genetics of Infectious Diseases Unit, Department of Genomes and Genetics, Paris, France.

    • Anavaj Sakuntabhai
  145. Centre National de la Recherche Scientifique, Unité de Recherche Associée 3012, Paris, France.

    • Anavaj Sakuntabhai
  146. Department of General Pediatrics, Medical University of Graz, Graz, Austria.

    • Werner Zenz,
    • Alexander Binder &
    • Daniela S Klobassa
  147. Faculty of Infectious and Tropical Disease, London School of Hygiene and Tropical Medicine, London, UK.

    • Martin L Hibberd
  148. Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany.

    • Stefan Herms &
    • Markus M Nöthen
  149. Department of Biomedicine, University of Basel, Basel, Switzerland.

    • Stefan Herms
  150. Division of Medical Genetics, University Hospital Basel, Basel, Switzerland.

    • Stefan Herms
  151. Institute of Human Genetics, University of Bonn, Bonn, Germany.

    • Markus M Nöthen
  152. Institute for Medical Informatics, Biometry and Epidemiology, University Hospital of Essen, University Duisburg-Essen, Essen, Germany.

    • Susanne Moebus
  153. Division of Ophthalmology, Stellenbosch University and Tygerberg Hospital, Cape Town, South Africa.

    • Robyn M Rautenbach &
    • Ari Ziskind
  154. Sydney Brenner Institute for Molecular Bioscience, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.

    • Michele Ramsay
  155. Department of Genetics, Eskisehir Osmangazi University, Meselik, Eskisehir, Turkey.

    • Çilingir Oguz
  156. Istanbul University Cerrahpasa Faculty of Medicine, Istanbul, Turkey.

    • Nevbahar Tamcelik,
    • Eray Atalay &
    • Bilge Batu
  157. DAMAGEN Genetic Diagnostic Center, Ankara, Turkey.

    • Dilek Aktas
  158. School of Medicine, Wayne State University, Detroit, Michigan, USA.

    • M Roy Wilson
  159. Center for Community Outreach and Policy, Stein Eye Institute, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.

    • Anne L Coleman
  160. Department of Cellular Biology and Anatomy, Center for Biotechnology and Genomic Medicine, James and Jean Culver Discovery Institute, Augusta University, Augusta, Georgia, USA.

    • Yutao Liu
  161. Vanderbilt Eye Institute, Vanderbilt University Medical Center, Nashville, Tennessee, USA.

    • Rachel W Kuchtey &
    • John Kuchtey
  162. Hamilton Glaucoma Center, Department of Ophthalmology and Shiley Eye Institute, University of California, San Diego, San Diego, California, USA.

    • Linda M Zangwill &
    • Robert N Weinreb
  163. Department of Genomic Medical Sciences, Kyoto Prefectural University of Medicine, Kyoto, Japan.

    • Masakazu Nakano &
    • Kei Tashiro
  164. Department of Frontier Medical Science and Technology for Ophthalmology, Kyoto Prefectural University of Medicine, Kyoto, Japan.

    • Shigeru Kinoshita
  165. Department of Ophthalmology, Radboud University Medical Centre, Nijmegen, the Netherlands.

    • Anneke I den Hollander &
    • Shazia Micheal
  166. Department of Ophthalmology, University of Turku and Turku University Hospital, Turku, Finland.

    • Eija Vesti
  167. Institute for Vision Research, University of Iowa, Iowa City, Iowa, USA.

    • John H Fingert
  168. Department of Ophthalmology and Visual Sciences, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA.

    • John H Fingert
  169. Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, Florida, USA.

    • Richard K Lee
  170. Department of Ophthalmology, Mayo Clinic, Rochester, Minnesota, USA.

    • Arthur J Sit
  171. Ophthalmic Consultants of Boston, Boston, Massachusetts, USA.

    • Bradford J Shingleton
  172. Institute of Biomedical Technologies, Italian National Research Centre (ITB-CNR), Segrate-Milano, Italy.

    • Daniele Cusi
  173. Department of Biosciences, COMSATS Institute of Information Technology, Islamabad, Pakistan.

    • Raheel Qamar
  174. Department of Biochemistry, Al-Nafees Medical College and Hospital, Isra University, Islamabad, Pakistan.

    • Raheel Qamar
  175. Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.

    • Peter Kraft
  176. John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, Florida, USA.

    • Margaret A Pericak-Vance
  177. Divisions of Genetics and Rheumatology, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.

    • Soumya Raychaudhuri
  178. Partners Center for Personalized Genetic Medicine, Boston, Massachusetts, USA.

    • Soumya Raychaudhuri
  179. Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.

    • Soumya Raychaudhuri
  180. Institute of Inflammation and Repair, University of Manchester, Manchester, UK.

    • Soumya Raychaudhuri
  181. Rheumatology Unit, Department of Medicine, Karolinska Institutet and Karolinska University Hospital Solna, Stockholm, Sweden.

    • Soumya Raychaudhuri
  182. Department of Ophthalmology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.

    • Steffen Heegaard
  183. Department of Pathology, Rigshospitalet, Eye Pathology Section, University of Copenhagen, Copenhagen, Denmark.

    • Steffen Heegaard
  184. Department of Ophthalmology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.

    • Tero Kivelä
  185. Department of Ophthalmology, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts, USA.

    • Louis R Pasquale &
    • Janey L Wiggs
  186. Institute of Computational Biology, Case Western Reserve University, Cleveland, Ohio, USA.

    • Jonathan L Haines
  187. Faculty of Medicine, University of Iceland, Reykjavik, Iceland.

    • Unnur Thorsteinsdottir,
    • Fridbert Jonasson &
    • Kari Stefansson
  188. Department of Ophthalmology, Landspitali University Hospital, Reykjavik, Iceland.

    • Fridbert Jonasson
  189. Einhorn Clinical Research Center, New York Eye and Ear Infirmary of Mount Sinai, New York, New York, USA.

    • Robert Ritch
  190. Dr. G.Venkataswamy Eye Research Institute, Aravind Medical Research Foundation, Aravind Eye Hospital, Madurai, India.

    • Periasamy Sundaresan
  191. Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.

    • Chiea Chuen Khor

Contributions

C.C.K., F.P., J.L.W., T.A. and M.O. jointly conceived the project. M.C.L., U.S.-S., M.Z., D.B., Y.F.C., X.Y.N., A.W.O.C., E.N.V., S.R.G., A.S.Y.C. and Y.C. conducted functional biological experiments. G.T., R.P.I., K.P.B., Z.L., G.P., S.S., J.N.C.B., S.U., Z.Y., L. Huang, J.N.F., R.Q.S., K.S.S., P. Kraft, I.J., A.G., M.A.P.-V., A.M.H., E.N.V., C.-Y.C. and J.L.H. conducted statistical analysis. S. Raychaudhuri provided critical input on statistical analysis. Z.X., S.Q.M., H.M.S., X.Y.C., S.Q.P. and K.K.H. conducted genotyping and sequencing experiments. T.A., M.O., T.M., A.H., S.E.W., Y.S.A., A.C.O., S. Nakano, K. Mori, A.P.C., K.H., S. Manabe, S. Kazama, T. Zarnowski, K.I., M. Irkec, M.C.-P., K. Sugiyama, P. Schlottmann, S.F.L., H.L., Y.N., M.B., K.H.P., S.C.C., K.Y., J.C.Z., J.B.J., R.S.K., S.A.P., N. Kalpana, R.G., L.V., T.D., D.P.E., L.d.J.M., M.P., S. Moghimi, R.I., D.B.-H., P. Kappelgaard, B. Wirostko, S.T., D.G., K.B., W.L.G., X.C., J.S., H.J., L.J., C.Q., H.Z., X.L., B.Z., Y.-X.W., L.X., S.L., P.R., G.C., S.T., G.M., N. Weisschuh, U.H., U.-C.W.-L., C.M., P. Founti, A. Chatzikyriakidou, T.P., E.A., A.L., R.S., N.P., V.S., R.V., C. Shivkumar, N. Kobakhidze, M.R.K., A.N.B., S.Y., A.I., H.N., N. Khatibi, A.F., C.L., L.D., T.R., P. Frezzotti, D.P., E.S., P. Manunta, Y.M., K. Miyata, T.H., E.C., S.I., A.Y., M.Y., Y.K., T.O., T. Sakurai, T. Sugimoto, H.C., M.A., M. Inatani, M.M., N.G., F.M., N.Y., Y.I., M.U., C. Sotozono, J.W.J., M.S., K.H.P., J.A., M.C.-A., S.M.E., A. Rafei, V.H.K.Y., M.I.K., O.O.O., A.O.A., I.U., A.O., N.K.-A., C.T., Y.S., W.S., S.O., N.J.U., I.A., H.A., F.A., E.K.-J., U.L., I.L., V.C., R.P.G., G.S.M., S. Roy, E.D., E. Silke, A. Rao, P. Sahay, P. Fornero, O.C., D.S., T. Zompa, R.A.M., E. Souzeau, P. Mitchell, J.J.W., A.W.H., M.C., J.G.C., S.Y.A., E.L.A., A.E., V.V., G.K., R.F., S.A.A.-O., O.O., L.A.A., B.C., R.H., S.-L.H., F.A.E.-D., R.G.-S., F.M.-T., A. Salas, K.P., L. Hansapinyo, B. Wanichwecharugruang, N.K., A. Sakuntabhai, H.X.N., G.T.T.N., T.V.N., W.Z., A.B., D.S.K., M.L.H., S.D., S. Herms, S. Heegaard, M.M.N., S. Moebus, R.M.R., A.Z., T.R.C., M.R., L.A., M.G., H.G.-I., P.P.R.-C., L.F.-V.C., C.O., N.T., E.A., B.B., D.A., B.K., M.R.W., A.L.C., Y.L., P.C., L. Herndon, R.W.K., J.K., K.C., C.J.C., A. Crandall, L.M.Z., T.Y.W., M.N., S. Kinoshita, A.I.d.H., E.V., J.H.F., R.K.L., A.J.S., B.J.S., N. Wang, D.C., R.Q., T. Kivela, A. Reis, F.E.K., R.N.W., L.R.P., F.J., R.R.A., R.R., T. Kubota, S. Micheal, F.T., J.E.C., K.A.-A., M.H., J.H.K., S. Nelson, D.M., P. Sundaresan, M.D. and K.T. were involved in sample collection, phenotyping and processing. U.T., G.T. and K. Stefansson supervised, conducted and provided analysis of deCODE data. The manuscript was written by C.C.K., with critical input from T.A., T.K., U.T., J.L.W., L.R.P. and F.P. All co-authors approved the manuscript for publication.

Competing financial interests

The authors declare no competing financial interests.

Corresponding authors

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Supplementary information

PDF files

  1. Supplementary Text and Figures (6,546 KB)

    Supplementary Figures 1–23, Supplementary Tables 1–5, 8–13 and 15–17, and Supplementary Note.

Excel files

  1. Supplementary Table 6 (14 KB)

    Genome-wide significant (P < 5 × 10−8) SNPs emerging from the LOXL1 deep sequencing effort after fixed-effects meta-analysis is performed.

  2. Supplementary Table 7 (14 KB)

    Details of all 63 amino acid substitutions (excluding the well-known rs3825942[G>A] for p.Gly153Asp and rs1048661[T>G] for p.Leu141Arg) that were detected from the deep resequencing of LOXL1 in 5,566 exfoliation syndrome cases and 6,279 controls from nine countries.

  3. Supplementary Table 14 (13 KB)

    LD regions around each of the seven genome-wide significant loci for exfoliation syndrome.

  4. Supplementary Data 1 (24 KB)

    Phased LOXL1 haplotypes from deep resequencing data.

  5. Supplementary Data 3 (24 KB)

    INRICH pathway analysis.

Zip files

  1. Supplementary Data 2 (35,681 KB)

    Summary statistics for the genome-wide association study.

Additional data