FOR IMMEDIATE RELEASE
7 JULY 2017
THE GENE MUTATION THAT CAN PREVENT GLAUCOMA
Singapore-led discovery of rare gene mutation and identification of five new susceptibility loci will help illuminate the disease biology
Singapore – In the largest study on any cause of glaucoma to date, an international research collaboration on Exfoliation Syndrome – a major form of glaucoma – has found a mutated gene that can prevent glaucoma, the leading cause of irreversible blindness worldwide. Jointly led by A*STAR’s Genome Institute of Singapore (GIS) and the Singapore Eye Research Institute (SERI) of the Singapore National Eye Centre (SNEC), the study involved more than 120,000 individuals from 36 countries across six continents. The study has recently been published in Nature Genetics.
Exfoliation Syndrome (XFS) is an age-related eye disease where abnormal whitish flakes are deposited in the front of the eye (iris, ciliary body, lens and zonules), and abnormalities in connective tissues may appear in parts of the body. The disease occurs globally in approximately 60 to 70 million people. In the eye, the disease often leads to an increase in eye pressure, or glaucoma, which can result in visual impairment and blindness.
Since the 2007 publication of an Icelandic study and subsequent validation attempts by research groups from around the world, it is known that common genetic variants in one gene, the LOXL1 gene, show a strong association with XFS. However, the association with common genetic markers at LOXL1 are reversed depending on ethnic group, thus rendering the health implications unclear. In this latest study, the researchers uncovered a rare protective mutation in the LOXL1 gene. The mutation, p.Y407F, was found to offer protection against XFS instead, thereby leading to the prevention of secondary glaucoma. The mutation offers a 25-fold protection against XFS, the largest ever seen for a common, complex disease.
 Common Sequence Variants in the LOXL1 Gene Confer Susceptibility to Exfoliation Glaucoma, Gudmar Thorleifsson, et al., Science, 2007.
“Naturally occurring genetic variants are hard to find, but once discovered, they pinpoint potential druggable targets. These are what we call 'accidents and experiments of nature’. The LOXL1 p.Y407F rare variant reported in this study is one of these examples,” explained Dr Khor Chiea Chuen, one of the study’s corresponding authors and Principal Investigator of Human Genetics at the GIS.
In addition, the researchers also discovered five new susceptibility gene loci in XFS – specifically POMP, TMEM136, AGPAT1, RBMS3 and SEMA6A. This will help deepen the researchers’ understanding of XFS and how the disease process works.
Prof Aung Tin, Executive Director of SERI and Deputy Medical Director of SNEC, and lead author of the paper said, “This was the largest ever genetic study for glaucoma, and with so many centres and patients from 35 countries involved, it was very challenging to coordinate the research with most of the work being done in Singapore. The findings are very exciting as it can lead to the development of new therapies for glaucoma.” Prof Aung is also Professor, Department of Ophthalmology at National University of Singapore.
Joint corresponding author Prof Janey L. Wiggs, who holds the post of Paul Austin Chandler Professor of Ophthalmology at the Harvard Medical School, commented, “This is a truly remarkable study that demonstrates the power of international collaboration. The results improve our understanding of glaucoma and also suggest important new therapeutic strategies for this common cause of blindness.” Prof Wiggs is also the Massachusetts Eye and Ear Infirmary’s Associate Chief of Ophthalmology Clinical Research, and Associate Director of Ocular Genomics Institute at Massachusetts Eye and Ear.
Executive Director of GIS, Prof Ng Huck Hui added, “By identifying the rare gene mutation, we have taken a significant step towards reducing the risk of glaucoma worldwide. A large-scale study like this reaffirms the importance and benefits of cross-institutional and cross-national collaborations, which will help us achieve improvements in human health.”
Glaucoma is the commonest cause of blindness amongst the elderly; understanding how this process happens will result in new medications to cure it.
ANNEX A – Notes to Editor
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Genome Institute of Singapore, A*STAR
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Singapore National Eye Centre
Tel: +65 6322 8394
About A*STAR’s Genome Institute of Singapore (GIS)
The Genome Institute of Singapore (GIS) is an institute of the Agency for Science, Technology and Research (A*STAR). It has a global vision that seeks to use genomic sciences to achieve extraordinary improvements in human health and public prosperity. Established in 2000 as a centre for genomic discovery, the GIS will pursue the integration of technology, genetics and biology towards academic, economic and societal impact.
The key research areas at the GIS include Human Genetics, Infectious Diseases, Cancer Therapeutics and Stratified Oncology, Stem Cell and Regenerative Biology, Cancer Stem Cell Biology, Computational and Systems Biology, and Translational Research,
The genomics infrastructure at the GIS is utilised to train new scientific talent, to function as a bridge for academic and industrial research, and to explore scientific questions of high impact.
For more information about GIS, please visit www.gis.a-star.edu.sg
About the Agency for Science, Technology and Research (A*STAR)
The Agency for Science, Technology and Research (A*STAR) is Singapore's lead public sector agency that spearheads economic oriented research to advance scientific discovery and develop innovative technology. Through open innovation, we collaborate with our partners in both the public and private sectors to benefit society.
As a Science and Technology Organisation, A*STAR bridges the gap between academia and industry. Our research creates economic growth and jobs for Singapore, and enhances lives by contributing to societal benefits such as improving outcomes in healthcare, urban living, and sustainability.
We play a key role in nurturing and developing a diversity of talent and leaders in our Agency and Research Institutes, the wider research community and industry. A*STAR oversees 18 biomedical sciences and physical sciences and engineering research entities primarily located in Biopolis and Fusionopolis.
For more information on A*STAR, please visit www.a-star.edu.sg
About Singapore Eye Research Institute (SERI)
Established in 1997, the Singapore Eye Research Institute (SERI) is Singapore’s national research institute for ophthalmic and vision research. It is the research arm of Singapore National Eye Centre, and affiliated to the National University of Singapore (NUS) and the Duke-NUS Medical School.
In two decades, SERI has grown from a team of 5 to over 225 staff, and more than 219 distinguished adjunct faculty members to become the largest eye research institute in the Asia-Pacific region. Collectively, our clinician-scientists and researchers have published more than 2,770 peer-reviewed papers supported by over S$227 million in competitive research grants. SERI has trained more than 180 current and past graduate students; and has been conferred over 407 national & international awards and 121 patents.
Today, SERI is recognized as a pioneering center for high quality eye research in Asia, with breakthrough discoveries that has translated to significant paradigm shift in eye care delivery.
ANNEX A: Notes to Editor
The research findings described in this media release can be found in the scientific journal Nature Genetics, under the title, “Genetic association study of exfoliation syndrome identifies a protective rare variant at LOXL1 and five new susceptibility loci” by Tin Aung1,2,3*, Mineo Ozaki4,5*, Mei Chin Lee1,6*, Ursula Schlötzer-Schrehardt7*, Gudmar Thorleifsson8*, Takanori Mizoguchi9*, Robert P. Igo Jr.10*, Aravind Haripriya11*, Susan E Williams*12, Yury S. Astakhov13*, Andrew C Orr14,15*, Kathryn P. Burdon16,17*, Satoko Nakano18*, Kazuhiko Mori19*, Khaled Abu-Amero20,21*, Michael Hauser1,22,23*, Zheng Li24, Gopalakrishnan Prakadeeswari25, Jessica N. Cooke Bailey10, Alina Popa Cherecheanu26,27, Jae H Kang28, Sarah Nelson29, Ken Hayashi30, Shin-ichi Manabe30, Shigeyasu Kazama31, Tomasz Zarnowski32, Kenji Inoue33, Murat Irkec34, Miguel Coca-Prados35,36,37, Kazuhisa Sugiyama38, Irma Järvelä39, Patricio Schlottmann40, S. Fabian Lerner41, Hasnaa Lamari42, Yildirim Nilgün43, Mukharram Bikbov44, Ki Ho Park45, Soon Cheol Cha46, Kenji Yamashiro47,48, Juan C. Zenteno49,50, Jost B. Jonas51,52, Rajesh S Kumar53, Shamira A Perera1,2, Anita S.Y. Chan1,2,6, Nino Kobakhidze54, Ronnie George55, Lingam Vijaya55, Tan Do56, Deepak P. Edward57,58, Lourdes de Juan Marcos59,60, Mohammad Pakravan61, Sasan Moghimi62, Ryuichi Ideta63, Daniella Bach-Holm64, Per Kappelgaard64, Barbara Wirostko65, Samuel Thomas65, Daniel Gaston15, Karen Bedard15, Wenda L Greer15, Zhenglin Yang66,67, Xueyi Chen68, Lulin Huang69,70, Jinghong Sang71, Hongyan Jia71, Liyun Jia52,71, Chunyan Qiao71, Hui Zhang71, Xuyang Liu72, Bowen Zhao52,71, Ya-Xing Wang52, Liang Xu71, Stéphanie Leruez73, Pascal Reynier74, George Chichua54, Sergo Tabagari75, Steffen Uebe76, Matthias Zenkel7, Daniel Berner7, Georg Mossböck77, Nicole Weisschuh78, Ursula Hoja7, Ulrich-Christoph Welge-Luessen7, Christian Mardin7, Panayiota Founti79, Anthi Chatzikyriakidou80, Theofanis Pappas79, Eleftherios Anastasopoulos79, Alexandros Lambropoulos80, Arkasubhra Ghosh81, Rohit Shetty82, Natalia Porporato83, Vijayan Saravanan25, Rengaraj Venkatesh84, Chandrashekaran Shivkumar85, Narendran Kalpana86, Sripriya Sarangapani87, Mozhgan R Kanavi88, Afsaneh Naderi Beni61, Shahin Yazdani61, Alireza lashay62, Homa Naderifar62, Nassim Khatibi62, Antonio Fea89, Carlo Lavia89, Laura Dallorto89, Teresa Rolle89, Paolo Frezzotti90, Daniela Paoli91, Erika Salvi92, Paolo Manunta93, Yosai Mori94, Kazunori Miyata94, Tomomi Higashide38, Etsuo Chihara95, Satoshi Ishiko96, Akitoshi Yoshida97, Masahide Yanagi98, Yoshiaki Kiuchi98, Tsutomu Ohashi99, Toshiya Sakurai100, Takako Sugimoto5, Hideki Chuman5, Makoto Aihara101, Masaru Inatani102, Masahiro Miyake47,103, Norimoto Gotoh104, Fumihiko Matsuda104, Nagahisa Yoshimura47,105, Yoko Ikeda19, Morio Ueno19, Chie Sotozono19, Jin Wook Jeoung45, Min Sagong46, Kyu Hyung Park106, Jeeyun Ahn107, Marisa Cruz-Aguilar49, Sidi M Ezzouhairi42, Abderrahman Rafei108, Yaan Fun Chong1, Xiao Yu Ng1, Shuang Ru Goh1, Yueming Chen1, Victor H.K. Yong1, Muhammad Imran Khan109, Olusola O Olawoye110.111, Adeyinka O Ashaye110.111, Idakwo Ugbede112, Adeola Onakoya113,114, Nkiru Kizor-Akaraiwe115,116, Chaiwat Teekhasaenee117, Yanin Suwan117, Wasu Supakontanasan117, Suhanya Okeke115,116, Nkechi Uche116,118 , Ifeoma Asimadu115,
Humaira Ayub119, Farah Akhtar120, Ewa Kosior-Jarecka32, Urszula Lukasik32, Ignacio Lischinsky121, Vania Castro122, Rodolfo Perez Grossmann123, Gordana Sunaric Megevand124, Sylvain Roy124, Edward Dervan125, Eoin Silke125, Aparna Rao126, Priti Sahay126, Pablo Fornero127, Osvaldo Cuello127, Delia Sivori41, Tamara Zompa128, Richard A Mills16, Emmanuelle Souzeau16, Paul Mitchell129, Jie Jin Wang129, Alex W Hewitt17,130, Michael Coote130, Jonathan G Crowston130, Sergei Y. Astakhov13, Eugeny L. Akopov13, Anton Emelyanov13,131, Vera Vysochinskaya131, Gyulli Kazakbaeva44, Rinat Fayzrakhmanov44, Saleh A. Al-Obeidan20, Ohoud Owaidhah57, Leyla Ali Aljasim57, Balram Chowbay132,133,134, Jia Nee Foo24,135, Raphael Q Soh24, Kar Seng Sim24, Zhicheng Xie24, Augustine W.O. Cheong24, Shi Qi Mok24, Hui Meng Soo24, Xiao Yin Chen24, Su Qin Peh24, Khai Koon Heng24, Rahat Husain2, Su-Ling Ho136, Axel M. Hillmer24, Ching-Yu Cheng1,2,3,6, Francisco A. Escudero-Domínguez59, Rogelio González-Sarmiento60,137, Frederico Martinon-Torres138,139, Antonio Salas140,141, Kessara Pathanapitoon142, Linda Hansapinyo142, Boonsong Wanichwecharugruang143, Naris Kitnarong144, Anavaj Sakuntabhai145,146, Hiệp X Nguyễn56, Giang T.T. Nguyễn56, Trình V Nguyễn56, Werner Zenz147, Alexander Binder147, Daniela S. Klobassa147, Martin L. Hibberd24,148, Sonia Davila24, Stefan Herms149,150,151, Markus M Nöthen149,152, Susanne Moebus153, Robyn M Rautenbach154, Ari Ziskind154, Trevor R Carmichael12, Michele Ramsay155, Lydia Álvarez35,36, Montserrat García35,36, Héctor González-Iglesias35,36, Pedro P. Rodríguez-Calvo35,36, Luis Fernández-Vega Cueto35,36, Çilingir Oguz156, Nevbahar Tamcelik157, Eray Atalay1,157, Bilge Batu157, Dilek Aktas158, Burcu Kasım34, M. Roy Wilson159, Anne L Coleman160, Yutao Liu161, Pratap Challa22, Leon Herndon22, Rachel W. Kuchtey162, John Kuchtey162, Karen Curtin65, Craig J. Chaya65, Alan Crandall65, Linda M. Zangwill163, Tien Yin Wong1,2,3, Masakazu Nakano164, Shigeru Kinoshita19,165, Anneke I. den Hollander109,166, Eija Vesti167, John H Fingert168,169, Richard K. Lee170, Arthur J. Sit171, Bradford J. Shingleton172, Ningli Wang52,71, Daniele Cusi173, Raheel Qamar174,175, Peter Kraft176, Margaret A. Pericak-Vance177, Soumya Raychaudhuri178,179,180,181,182, Steffen Heegaard183,184, Tero Kivelä185, André Reis76, Friedrich E. Kruse7, Robert N Weinreb163, Louis R. Pasquale28,186, Jonathan L. Haines10,187, Unnur Thorsteinsdottir 8,188, Fridbert Jonasson188,189*, R Rand Allingham1,22*, Dan Milea1,2,6*, Robert Ritch190*, Toshiaki Kubota18*, Kei Tashiro164*, Eranga N Vithana1,3*, Shazia Micheal166*, Fotis Topouzis79*, Jamie E. Craig16*, Michael Dubina13,131*, Periasamy Sundaresan191*, Kari Stefansson8,188*, Janey L Wiggs186*, Francesca Pasutto76*, Chiea Chuen Khor1,24,192*.
* These authors all contributed equally to this work.
1. Singapore Eye Research Institute, Singapore
2. Singapore National Eye Center, Singapore
3. Dept of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
4. Ozaki Eye Hospital, Hyuga, Miyazaki, Japan.
5. Department of Ophthalmology, Faculty of Medicine University of Miyazaki, Miyazaki, Japan
6. Academic Clinical Program for Ophthalmology and Visual Sciences, Office of Clinical & Academic Faculty Affairs, Duke-NUS Graduate Medical School, Singapore
7. Department of Ophthalmology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
8. deCODE genetics, Sturlugata 8, 101 Reykjavic, Iceland
9. Mizoguchi Eye Hospital, Sasebo, Japan.
10. Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, Ohio, USA.
11. Aravind Eye Hospital, Madurai, India.
12. Division of Ophthalmology, University of the Witwatersrand, Johannesburg, South Africa.
13. Pavlov First Saint Petersburg State Medical University, St. Petersburg, Russia
14. Department of Ophthalmology, Dalhousie University, Halifax, Nova Scotia, Canada
15. Department of Pathology, Dalhousie University, Halifax, Nova Scotia, Canada
16. Department of Ophthalmology, Flinders University, Adelaide, SA, Australia
17. Menzies Institute for Medical Research, University of Tasmania, Australia
18. Department of Ophthalmology, Oita University Faculty of Medicine, Oita, Japan
19. Department of Ophthalmology, Kyoto Prefectural University of Medicine, Kyoto, Japan.
20. Department of Ophthalmology, College of Medicine, King Saud University, Riyadh, Saudi Arabia
21. Department of Ophthalmology, College of Medicine, University of Florida, Jacksonville, FL, USA
22. Department of Ophthalmology, Duke University Eye Center, Durham, NC, USA
23. Department of Medicine, Duke University Medical Center, Durham, NC, USA
24. Genome Institute of Singapore, Singapore
25. Department of Genetics, Aravind Medical Research Foundation, Madurai, India
26. “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania
27. University Emergency Hospital, Department of Ophthalmology, Bucharest, Romania
28. Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
29. Department of Biostatistics, University of Washington, Seattle, WA, USA
30. Hayashi Eye Hospital, 23-35, Hakataekimae-4, Hakata-ku, Fukuoka, Japan
31. Shinjo Eye Clinic, 889-1, Mego, Simokitakatamachi, Miyazaki-shi, Miyazaki, Japan
32. Department of Diagnostics and Microsurgery of Glaucoma, Medical University, Lublin, Poland, Chmielna 1, 20-079 Lublin, Poland.
33. Inoue Eye Hospital, 4-3 Kanda-Surugadai, Chiyoda-ku, Tokyo, Japan.
34. Department of Ophthalmology, Hacettepe University, Faculty of Medicine, Ankara, Turkey
35. Fernández-Vega University Institute and Foundation of Ophthalmological Research, University of Oviedo, Oviedo, Spain.
36. Fernández-Vega Ophthalmological Institute, Avda. Dres. Fernández-Vega, 34, Oviedo 33012, Spain
37. Department of Ophthalmology and Visual Science, Yale University School of Medicine, 300 George
St, 8100A, New Haven, CT 06510, USA.
38. Department of Ophthalmology Kanazawa University Graduate School of Medical Science, 13-1 Takara-machi, Kanazawa, Japan
39. Department of Medical Genetics, University of Helsinki, Helsinki, Finland.
40. Organización Médica de Investigación, Uruguay 725 - PB, Buenos Aires, Argentina
41. Fundacion para el Estudio del Glaucoma, Marcelo T de Alvear 2010 - 2A, Buenos Aires, Argentina
42. Clinique Spécialisée en Ophtalmologie Mohammedia, Mohammedia, Morocco
43. Department of Ophthalmology, Eskisehir Osmangazi University, Meselik, Eskisehir, Turkey
44. Ufa Eye Research Institute, Ufa, Republic of Bashkortostan, Russia.
45. Department of Ophthalmology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, South Korea
46. Department of Ophthalmology, Yeungnam University College of Medicine, Daegu, South Korea
47. Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Kyoto, Japan
48. Department of Ophthalmology, Otsu Red Cross Hospital, Otsu, Japan 520-8511
49. Genetics Department, Institute of Ophthalmology "Conde de Valenciana" Mexico City, Mexico, Chimalpopoca 14, Col. Obrera, CP 06800, Mexico City, Mexico
50. Biochemistry Department, Faculty of Medicine, UNAM, Mexico City, Mexico
51. Department of Ophthalmology, Medical Faculty Mannheim of the Ruprecht-Karls-University of Heidelberg, Mannheim, Germany.
52. Beijing Institute of Ophthalmology and Visual Science Key Lab Beijing-China, Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing, China
53. Narayana Nethralaya Eye Hospital, 121/C,Chord Road,Rajajinagar, 1st R Block, Bangalore 560 010, India.
54. Chichua Medical Center Mzera LLC, Tiblisi, Georgia
55. Jadhavbhai Nathamal Singhvi Department of Glaucoma, Medical Research Foundation,Sankara Nethralaya, 18, College Road, Chennai, India
56. Vietnam National Institute of Ophthalmology, Hanoi, Vietnam
57. King Khaled Eye Specialist Hospital, Riyadh, Kingdom of Saudi Arabia
58. Department of Ophthalmology and Visual Sciences, Illinois Eye and Ear Infirmary, College of Medicine, University of Illinois at Chicago, Chicago, IL, United States
59. Department of Ophthalmology, University Hospital of Salamanca, Salamanca, Spain
60. Institute for Biomedical Research of Salamanca (IBSAL), Spain
61. Ophthalmic Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
62. Farabi eye hospital, Tehan University Eye Research Center. Tehran University of Medical Sciences, Tehran, Iran.
63. Ideta Eye Hospital, Kumamoto City, Japan.
64. Eye Clinic, Rigshospitalet – Glostrup, Denmark
65. John A. Moran Eye Center, Dept. of Ophthalmology, University of Utah, Salt Lake City, Utah, USA
66. Sichuan Provincial Key Laboratory for Human Disease Gene Study, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan, China.
67. School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, China.
68. Department of Ophthalmology,the First Affiliated Hospital of Xinjiang Medical University,Urumchi 830054;2 Xinjiang Uygur Autonomous Region, China
69. Center for Human Molecular Biology & Genetics, The Institute of Laboratory Medicine, Sichuan Academy of Medical Sciences & Sichuan Provincial People’s Hospital, Chengdu, Sichuan, China.
70. Sichuan Translational Research Hospital, Chinese Academy of Sciences, Chengdu 610072, Sichuan, China
71. Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing Ophthalmology & Visual Science Key Lab, Beijing, China
72. Shenzhen Key Laboratory of Ophthalmology,Shenzhen Eye Hospital,Jinan University, Shenzhen, China.
73. Département d’Ophtalmologie, Centre Hospitalier Universitaire, F-49933 Angers, France
74. Département de Biochimie et Génétique, Centre Hospitalier Universitaire, F-49933 Angers, France
75. David Tvildiani Medical University, Tbilisi, Georgia
76. Institute of Human Genetics, Friedrich-Alexander-Universität, Erlangen-Nürnberg, Erlangen, Germany
77. Department of Ophthalmology, Medical University Graz, Graz, Austria
78. Institute for Ophthalmic Research, Centre for Ophthalmology, University of Tuebingen, Tuebingen, Germany.
79. Department of Ophthalmology, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece
80. Laboratory of General Biology, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece
81. GROW Research Lab, Narayana Nethralaya Foundation, Bangalore, India
82. Narayana Nethralaya Eye Hospital, 121/C,Chord Road,Rajajinagar, 1st R Block, Bangalore 560 010, India.
83. Santa Lucia Eye Hospital from Buenos Aires, Argentina.
84. Aravind Eye Hospital, Pondicherry, India
85. Aravind Eye Hospital, Tirunelveli, India
86. Aravind Eye Hospital, Coimbatore, India
87. Vision Research Foundation, 18, College Road, Chennai, India
88. Ocular Tissue Engineering Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
89. Dipartimento di Scienze Chirurgiche, Universita’ di Torino, Turin, Italy.
90. Ophthalmology Unit Department of Medicine, Surgery and Neuroscience, University of Siena, Siena, Italy
91. Department of Ophthalmology, Monfalcone Hospital, Gorizia, Italy
92. Department of Health Sciences, University of Milan, Italy
93. Department of Nephrology, University Vita-Salute San Raffaele, Milano, Italy
94. Miyata Eye Hospital, 6-3, Kurahara, Miyakonojo, Miyazaki 885-0051 Japan
95. Sensho-kai Eye Institute, Minamiyama 50-1, Iseda, Uji, Kyoto 611-0043, Japan
96. Department of Medicine and Engineering Combined Research Institute,Asahikawa Medical University, Japan
97. Department of Ophthalmology, Asahikawa Medical University, 4-5 Nishikagura, Asahikawa 078-8510 Japan
98. Hiroshima University, Department of Ophthalmology and Visual Sciences,1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
99. Ohashi eye center, Kita2-1 Hondori6 Shiroishi-ku Sapporo 003-0027 Japan
100. Tane Memorial Eye Hospital,1-1-39, Sakaigawa, Nishi-ku, Osaka, 550-0024, Japan
101. Department of Ophthalmology, University of Tokyo, Bunkyo, Tokyo 113-8655, Japan
102. Department of Ophthalmology, Faculty of Medical Science, University of Fukui, 23-3 Shimoaizuki, Matsuoka, Eiheiji, Yoshida, Fukui, 910-1193, Japan
103. Japan Agency for Medical Research and Development, Tokyo, Japan 100-0004
104. Center for Genomic Medicine/Inserm U.852, Kyoto University Graduate School of Medicine, Kyoto, Japan 606-8507
105. Tazuke Kofukai Foundation, Medical Research Institute, Kitano Hospital, Osaka, Japan 530-8480
106. Department of Ophthalmology, Seoul National University Bundang Hospital, Gyeonggi, South Korea.
107. Department of Ophthalmology, Seoul Metropolitan Government Seoul National University Boramae Medical Center, Seoul, South Korea.
108. Laboratoires RAFEI, Mohammedia, Morocco
109. Department of Human Genetics, Radboud University Medical Centre, Nijmegen, the Netherlands
110. Department of Ophthalmology, College of Medicine, University of Ibadan, Ibadan, Nigeria
111. Department of Ophthalmology, University College Hospital, Ibadan, Nigeria
112. ECWA Eye Hospital, Kano, Nigeria
113. Department of Ophthalmology University of Lagos, Lagos, Nigeria
114. Guinness Eye Centre Lagos University Teaching Hospital, Lagos Nigeria
115. Department of Ophthalmology, ESUT Teaching Hospital Parklane, Park Avenue, GRA. Enugu, Nigeria
116. The Eye Specialists Hospital, 11 Church View, GRA, Enugu, Nigeria.
117. Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
118. Department of Ophthalmology, University of Nigeria Teaching Hospital, Ituku-Ozalla, Enugu, Nigeria.
119. Department of Environmental Sciences, COMSATS Institute of Information Technology, Abbottabad Campus, Pakistan.
120. Pakistan Institute of Ophthalmology, Al-Shifa Trust Eye Hospital, Rawalpindi, Pakistan
121. Centro Oftalmologico Lischinsky, Tucuman, Argentina
122. Universidad Peruana Cayetano Heredia- Hospital Nacional Arzobispo Loayza, Lima – Perú.
123. Instituto de Glaucoma y Catarata, Lima – Perú
124. Clinical Research Centre Adolphe de Rothschild, Société Médicale de Beaulieu, Geneva, Switzerland.
125. Mater Misericordiae University Hospital, Eccles St, Dublin 7, Ireland
126. Shri Mithu Tulsi Chanrai campus, LV Prasad Eye Institute, Patia, Bhubaneswar, Odisha, India
127. Hospital Cordoba, Cordoba, Argentina
128. Centro Oftalmologico Charles, Buenos Aires, Argentina
129. Centre for Vision Research, Department of Ophthalmology and Westmead Institute for Medical Research, University of Sydney, NSW Australia
130. Centre for Eye Research Australia (CERA), University of Melbourne, Royal Victorian Eye and Ear Hospital, Melbourne, Victoria, Australia
131. St. Petersburg Academic University, St. Petersburg, Russia
132. Clinical Pharmacology, SingHealth, Singapore, Singapore
133. Clinical Pharmacology Laboratory, National Cancer Centre, Singapore
134. Office of Clinical Sciences, Duke-NUS Medical School, Singapore
135. Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore.
136. Department of Ophthalmology, Tan Tock Seng Hospital, Singapore
137. Molecular Medicine Unit. Department of Medicine. University of Salamanca. Salamanca, Spain
138. Translational Pediatrics and Infectious Diseases, Hospital Clínico Universitario de Santiago, Santiago de Compostela, Spain
139. GENVIP Research Group, Instituto de Investigación Sanitaria de Santiago, Galicia, Spain
140. Unidade de Xenética, Departamento de Anatomía Patolóxica e Ciencias Forenses, Spain
141. Instituto de Ciencias Forenses, Facultade de Medicina, Universidade de Santiago de Compostela, Santiago de Compostela, Galicia, Spain.
142. Department of Ophthalmology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
143. Department of Ophthalmology, Rajavithi Hospital, Bangkok, Thailand
144. Department of Ophthalmology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.
145. Institut Pasteur, Functional Genetics of Infectious Diseases Unit, Department of Genomes and Genetics, Paris, 75015, France
146. Centre National de la Recherche Scientifique, Unité de Recherche Associée 3012, Paris, France.
147. Department of General Pediatrics, Medical University of Graz, Graz, Austria
148. Faculty of Infectious and Tropical Disease, London School of Hygiene and Tropical Medicine, Keppel Street, London, WC1E 7HT, UK
149. Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany
150. Department of Biomedicine, University of Basel, Basel, Switzerland
151. Division of Medical Genetics, University Hospital Basel, Basel, Switzerland
152. Institute of Human Genetics, University of Bonn, Bonn, Germany
153. Institute for Medical Informatics, Biometry and Epidemiology, University Hospital of Essen, University Duisburg-Essen, Essen, Germany
154. Division of Ophthalmology, Stellenbosch University and Tygerberg Hospital, Cape Town, South Africa
155. Sydney Brenner Institute for Molecular Bioscience, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
156. Department of Genetics, Eskisehir Osmangazi University, Meselik, Eskisehir, Turkey.
157. Istanbul University Cerrahpasa Faculty of Medicine, Istanbul, Turkey.
158. DAMAGEN Genetic Diagnostic Center, Ankara, Turkey
159. School of Medicine, Wayne State University, Detroit, Michigan, USA
160. Center for Community Outreach and Policy, Stein Eye Institute, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095 USA
161. Department of Cellular Biology and Anatomy, Center for Biotechnology and Genomic Medicine, James & Jean Culver Discovery Institute, Augusta University, Augusta, Georgia, USA.
162. Vanderbilt Eye Institute, Vanderbilt University Medical Center, Nashville, Tennessee 37232-8808, USA
163. Hamilton Glaucoma Center, Department of Ophthalmology and Shiley Eye Institute, University of California, San Diego, USA
164. Department of Genomic Medical Sciences, Kyoto Prefectural University of Medicine, Kyoto, Japan
165. Department of Frontier Medical Science and Technology for Ophthalmology, Kyoto Prefectural University of Medicine, Kyoto, Japan
166. Department of Ophthalmology, Radboud University Medical Centre; Nijmegen, the Netherlands
167. Department of Ophthalmology, University of Turku and Turku University Hospital, Turku, Finland
168. Institute for Vision Research, University of Iowa, Iowa City, USA
169. Department of Ophthalmology and Visual Sciences, Carver College of Medicine, University of Iowa, Iowa City, USA
170. Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, Florida, USA.
171. Department of Ophthalmology, Mayo Clinic, Rochester, Minnesota, USA
172. Ophthalmic consultants of Boston, Boston, MA, USA
173. Institute of Biomedical Technologies, Italian National Research Centre (ITB-CNR), Segrate-Milano, Italy.
174. Department of Biosciences, COMSATS Institute of Information Technology, Islamabad Campus, Park Road, Tarlai Kalan, Islamabad, Pakistan
175. Department of Biochemistry, Al-Nafees Medical College & Hospital, Isra University, Islamabad, Pakistan
176. Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA
177. John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, Florida, USA
178. Divisions of Genetics and Rheumatology, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, USA
179. Partners Center for Personalized Genetic Medicine, Boston, USA
180. Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, USA
181. Institute of Inflammation and Repair, University of Manchester, Manchester, UK
182. Rheumatology Unit, Department of Medicine, Karolinska Institutet and Karolinska University Hospital Solna, Stockholm, Sweden.
183. Department of Ophthalmology, Rigshospitalet, University of Copenhagen, Denmark.
184. Department of Pathology, Rigshospitalet, Eye Pathology Section, University of Copenhagen, Denmark.
185. Department of Ophthalmology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
186. Department of Ophthalmology, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts, USA.
187. Institute of Computational Biology, Case Western Reserve University, Cleveland, Ohio, USA.
188. Faculty of Medicine, University of Iceland, Reykjavik, Iceland;
189. Department of Ophthalmology, Landspitali University Hospital, Reykjavik, Iceland
190. Einhorn Clinical Research Center, New York Eye and Ear Infirmary of Mount Sinai, New York, NY USA
191. Dr. G.Venkataswamy Eye Research Institute, Aravind Medical Research Foundation, Aravind Eye Hospital, No.1 Anna Nagar, Madurai-625 020, Tamilnadu, India
192. Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
Correspondence should be addressed to T. Aung (email@example.com), F. Pasutto (Francesca.Pasutto@uk-erlangen.de), J. L. Wiggs (Janey_Wiggs@meei.harvard.edu), or to C.C. Khor (firstname.lastname@example.org).