Findings provide deeper understanding of the disease which affects mainly ageing Asians, and open up new possibilities for the delivery of precision medicine
– An international research collaboration has revealed eight genes strongly associated with primary angle-closure glaucoma (PACG), the most prevalent form of glaucoma in Singapore, and Asia. These eight genes provide unexpected insights into the disease process of glaucoma, and how the shape of the eye could contribute to the disease even in currently healthy, asymptomatic people. The collaboration was jointly led by Dr Khor Chiea Chuen from A*STAR’s Genome Institute of Singapore (GIS) and Prof Aung Tin from Singapore Eye Research Institute (SERI), Singapore National Eye Centre (SNEC) and National University of Singapore (NUS).
The study involved more than 10,000 patients from 24 countries and the findings were reported in the prestigious scientific journal Nature Genetics. This paves the way to identify potential new drug targets to treat glaucoma, and build up genetic predictors that could help to screen and to direct treatment for individuals at risk of becoming blind from glaucoma.
Although it is preventable, glaucoma is the most common cause of irreversible blindness worldwide. PACG is responsible for a high proportion of blindness in Asia; with up to 80 percent of the estimated 15 million people afflicted with PACG living in Asia.
Epidemiological risk factors of PACG include advancing age, the female gender, as well as being of East Asian ethnicity. There are also ocular risk factors such as hyperopia and smaller anatomical dimensions of the eye. Having seen glaucoma patients at the SNEC and SERI for more than 20 years, Prof Aung noticed that PACG is fairly common in elderly Singaporean Chinese, and that the disease appears to run in families, thus raising the possibility that there could also be a hereditable basis for PACG.
For much of the past decade, the search for susceptibility genes for PACG has not been fruitful mainly because earlier genomic technology and methods did not allow deep and broad searches across the entire genome to occur concurrently. Recent advances in genomic technology have made possible an unprecedentedly broad and unbiased search for genes associated with disease in the human genome, sparking GIS and SERI/SNEC to collaborate again in the search for human genetic variants which could cause PACG. Other collaborating centres in Singapore include National University Health System, Tan Tock Seng Hospital and Changi General Hospital.
Prof Aung, Executive Director of SERI and the consortium leader who initiated the project, said, “It was very exciting but also challenging to coordinate this project from Singapore as it involved so many samples from more than 100 centres in 24 countries around the world. We hope our findings will be a major contribution to the understanding of PACG, which is a particularly important cause of glaucoma and visual loss/blindness in Singapore and Asia. This research is a great example of successful international multi-centre collaborative research; we are grateful to all our study participants and collaborators, as well as funding bodies in Singapore such as National Research Foundation and National Medical Research Council, who funded this work.”
Dr Khor, co-lead author of the study and Principal Investigator of Human Genetics at the GIS, said, “Research on complex genetic diseases such as PACG needs to be undertaken in large enough numbers so that as many people as possible are represented. The findings we present here are averaged across more than 10,000 patients from 24 countries.”
“This very large multi-ethnic study of angle-closure glaucoma has identified five new genes contributing to this important cause of blindness. This unprecedented analysis provides a comprehensive genetic profile of angle-closure glaucoma, and these findings will suggest important areas of research that may lead to new strategies to screen, prevent and treat this devastating disease,” added Prof Janey L. Wiggs, who holds the post of Paul Austin Chandler Professor of Ophthalmology at the Harvard Medical School. Prof Wiggs is also the Massachusetts Eye and Ear Infirmary’s Associate Chief of Ophthalmology Clinical Research, and Associate Director of Howe Laboratory.
GIS Executive Director Prof Ng Huck Hui said, “As Singapore faces the challenge of a rapidly ageing population, the need to research the genetics of age-related diseases, like glaucoma, also increases. Considering how prevalent PACG is in Asian populations, this discovery is significant as researchers continue to work towards precision medicine. It allows for better clinical decision-making which ultimately leads to improved healthcare outcomes for the public. This collaboration also reaffirms the importance of cross-institutional efforts; bringing our capabilities together results in high-impact research.”
The study leaders: Prof Aung Tin (left) of Singapore Eye Research Institute and Dr Khor Chiea Chuen (right) of the Genome Institute of Singapore
Notes to Editor:
The research findings described in this media release can be found in the scientific journal Nature Genetics, under the title, “Genome-wide association study identifies five new susceptibility loci for primary angle closure glaucoma” by Chiea Chuen Khor1,2,3,124, Tan Do 4,124, Hongyan Jia5,124, Masakazu Nakano6,124, Ronnie George7,124, Khaled Abu-Amero8,9,124, Roopam Duvesh10,124, Li Jia Chen11,124, Zheng Li1, Monisha E Nongpiur2, Shamira A Perera2, Chunyan Qiao5, Hon-Tym Wong12, Hiroshi Sakai13, Mônica Barbosa de Melo14, Mei-Chin Lee2, Anita S Chan2, Yaakub Azhany15, Thi Lam Huong Dao4, Yoko Ikeda16, Rodolfo A Perez-Grossmann17, Tomasz Zarnowski18, Alexander C Day19,20,21, Jost B Jonas22, Pancy O.S. Tam11, Tuan Anh Tran23, Humaira Ayub24, Farah Akhtar25, Shazia Micheal26 , Paul T K Chew27, Leyla A Aljasim28, Tanuj Dada29, Tam Thi Luu30, Mona S Awadalla31, Naris Kitnarong32, Boonsong Wanichwecharugruang33,34, Yee Yee Aung35, Jelinar Mohamed-Noor36, Saravanan Vijayan10, Sripriya Sarangapani37, Rahat Husain2,38, Aliza Jap2,38, Mani Baskaran2, David Goh2, Daniel H Su2, Huaizhou Wang5, Vernon K Yong12, Leonard W Yip12, Tuyet Bach Trinh23, Manchima Makornwattana39, Thanh Thu Nguyen40, Edgar U. Leuenberger41,42, Ki-Ho Park43, Widya Artini Wiyogo44,45, Rajesh S Kumar46, Celso Tello47, Yasuo Kurimoto48, Suman S Thapa49, Kessara Pathanapitoon50, John F Salmon51, Yong Ho Sohn52, Antonio Fea53, Mineo Ozaki54,55, Jimmy S M Lai56, Visanee Tantisevi57, Chaw Chaw Khaing58, Takanori Mizoguchi59, Satoko Nakano60, Chan-Yun Kim61, Guangxian Tang62, Sujie Fan63, Renyi Wu64, Hailin Meng65, Thi Thuy Giang Nguyen4, Tien Dat Tran4, Morio Ueno16, Jose Maria Martinez66, Norlina Ramli67,68, Yin Mon Aung69,70, Rigo Daniel Reyes71,72, Stephen A Vernon73,74, Seng Kheong Fang75, Zhicheng Xie1, Xiao Yin Chen1, Jia Nee Foo1, Kar Seng Sim1, Tina T Wong2, Desmond T Quek2, Rengaraj Venkatesh76, Srinivasan Kavitha76, Subbiah R Krishnadas77, Nagaswamy Soumittra37, Balekudaru Shantha7, Boon-Ang Lim12, Jeanne Ogle12, José P C de Vasconcellos78, Vital P Costa77, Ricardo Y Abe77, Bruno B de Souza14, Chelvin C Sng27, Maria C Aquino27, Ewa Kosior-Jarecka18, Guillermo Barreto Fong79, Vania Castro Tamanaja80, Ricardo Fujita81, Yuzhen Jiang19–21, Naushin Waseem19,21, Sancy Low19–21, Huan Nguyen Pham23, Sami Al-Shahwan28, E Randy Craven28,82, Muhammad Imran Khan83, Rrima Dada29, Kuldeep Mohanty29, Muneeb A Faiq29, Alex W Hewitt84,85, Kathryn P Burdon31,84, Eng Hui Gan36, Anuwat Prutthipongsit39, Thipnapa Patthanathamrongkasem39, Mary Ann T Catacutan41, Irene R Felarca41, Chona S Liao41, Emma Rusmayani44, Vira Wardhana Istiantoro44, Giulia Consolandi53, Giulia Pignata53, Carlo Lavia53, Prin Rojanapongpun57, Lerprat Mangkornkanokpong86, Sunee Chansangpetch86, Jonathan C H Chan87, Bonnie N K Choy56, Jennifer W H Shum56, Hlaing May Than88, Khin Thida Oo69,70, Aye Thi Han69,70, Victor H Yong2, Xiao-Yu Ng2, Shuang Ru Goh2, Yaan Fun Chong2, Martin L Hibberd1, Mark Seielstad89, Eileen Png1, Sarah J Dunstan90,91, Nguyen Van Vinh Chau92, Jinxin Bei93,94, Yi Xin Zeng93–95, Abhilasha Karkey96, Buddha Basnyat96, Francesca Pasutto97, Daniela Paoli98, Paolo Frezzotti99, Jie Jin Wang100, Paul Mitchell100, John H Fingert101,102, R Rand Allingham2,103, Michael A Hauser2,103,104, Soon Thye Lim105, Soo Hong Chew106, Richard P Ebstein107, Anavaj Sakuntabhai108,109, Kyu Hyung Park110, Jeeyun Ahn111, Greet Boland112, Harm Snippe112, Richard Stead73, Raquel Quino71, Su Nyunt Zaw69,70, Urszula Lukasik18, Rohit Shetty46, Mimiwati Zahari67,68, Hyoung Won Bae61, Nay Lin Oo58, Toshiaki Kubota60, Anita Manassakorn57, Wing Lau Ho86, Laura Dallorto53, Young Hoon Hwang52, Christine A Kiire51, Masako Kuroda48, Zeiras Eka Djamal44, Jovell Ian M Peregrino41, Arkasubhra Ghosh46,113, Jin Wook Jeoung43, Tung S Hoan40, Nuttamon Srisamran39, Thayanithi Sandragasu36, Saw Htoo Set35, Vi Huyen Doan30, Shomi S Bhattacharya21, Ching-Lin Ho2, Donald T Tan2, Ramanjit Sihota29, Seng-Chee Loon27, Kazuhiko Mori16, Shigeru Kinoshita16, Anneke I den Hollander26,83 , Raheel Qamar24,114, Ya-Xing Wang115, Yik Y Teo1,116–119, E-Shyong Tai116,120, Curt Hartleben-Matkin121, David Lozano-Giral122, Seang Mei Saw2,116, Ching-Yu Cheng2,27, Juan C Zenteno122,123, Chi Pui Pang11, Huong T T Bui23, Owen Hee12, Jamie E Craig31, Deepak P Edward28,82, Michiko Yonahara13, Jamil Miguel Neto78, Maria L Guevara-Fujita81, Liang Xu115, Robert Ritch47, Ahmad Tajudin Liza-Sharmini15, Tien Y Wong2, Saleh Al-Obeidan8, Nhu Hon Do4,125, Periasamy Sundaresan10,125, Clement C Tham11,125, Paul J Foster19–21,125, Lingam Vijaya2,7,125, Kei Tashiro6,125, Eranga N Vithana2,125, Ningli Wang5,115,125, Tin Aung2,27,125
1. Genome Institute of Singapore, A-STAR, Singapore
2. Singapore Eye Research Institute, Singapore National Eye Centre, and Eye ACP, Duke-NUS, Singapore
3. Department of Biochemistry, National University of Singapore, Singapore
4. Vietnam National Institute of Ophthalmology, Hanoi, Vietnam
5. Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing Ophthalmology & Visual Science Key Lab, Beijing, China
6. Department of Genomic Medical Sciences, Kyoto Prefectural University of Medicine, Kyoto, Japan.
7. Jadhavbhai Nathamal Singhvi Department of Glaucoma, Medical Research Foundation, Sankara Nethralaya, Chennai, India
8. Department of Ophthalmology, College of Medicine, King Saud University, Riyadh, Saudi Arabia
9. Department of Ophthalmology, College of Medicine, University of Florida, Jacksonville, FL, USA
10. Department of Genetics, Aravind Medical Research Foundation, Madurai, Tamilnadu, India.
11. Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Hong Kong
12. Department of Ophthalmology, Tan Tock Seng Hospital, NHG Eye Institute, Singapore
13. Department of Ophthalmology, University of the Ryukyus, Okinawa, Japan
14. Center of Molecular Biology and Genetic Engineering, University of Campinas, Campinas, SP, Brazil
15. Department of Ophthalmology, School of Medical Sciences, Health campus, Universiti Sains Malaysia and Hospital Universiti Sains Malaysia, Kelantan, Malaysia
16. Department of Ophthalmology, Kyoto Prefectural University of Medicine, Kyoto, Japan.
17. Instituto de Glaucoma y Catarata, Lima – Perú
18. Department of Diagnostics and Microsurgery of Glaucoma, Medical University, Lublin, Poland
19. NIHR Biomedical Research Centre for Ophthalmology at Moorfields Eye Hospital and University College London Institute of Ophthalmology, London, UK
20. Glaucoma Service, Moorfields Eye Hospital NHS Foundation Trust, City Road, London, UK
21. Division of Genetics, UCL Institute of Ophthalmology, Bath Street, London, UK
22. Department of Ophthalmology, Medical Faculty Mannheim of the Ruprecht Karls University Heidelberg, Heidelberg, Germany.
23. Ho Chi Minh City Eye Hospital, HCM City, Vietnam
24. Department of Biosciences, COMSATS Institute of Information Technology, Islamabad, Pakistan
25. Pakistan Institute of Ophthalmology, Al-Shifa Trust Eye Hospital, Rawalpindi, Pakistan
26. Department of Ophthalmology, Radboud University Medical Centre; Nijmegen, the Netherlands
27. Department of Ophthalmology, National University Health System, Yong Loo Lin School of Medicine, National University of Singapore
28. King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia
29. All India Institute of Medical Sciences, New Delhi, India
30. Department of glaucoma, Da Nang Eye Hospital, Da Nang city, Viet Nam.
31. Department Of Ophthalmology, Flinders University, Flinders Medical Centre, Adelaide, South Australia, Australia
32. Department of Ophthalmology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
33. Glaucoma Services, Department of Ophthalmology, Rajavithi Hospital, Bangkok, Thailand
34. Rangsit Medical College, Bangkok, Thailand
35. Mandalay Eye department, Mandalay Eye ENT hospital, University of Medicine Mandalay, Union of Myanmar
36. Department of Ophthalmology, Hospital Kuala Lumpur, Kuala Lumpur, Malaysia
37. Vision Research Foundation, Sankara Nethralaya, Chennai, India
38. Changi General Hospital, Singapore
39. Department of Ophthalmology, Thammasat University Faculty of Medicine, Rangsit, Thailand
40. Viet Tiep General Hospital, Hai Phong, Vietnam
41. Asian Eye Institute, Manila, Philippines
42. University of the East, Manila, Philippines
43. Department of Ophthalmology, Seoul National University College of Medicine, Seoul, South Korea
44. Glaucoma Service Jakarta Eye Center, Jakarta, Indonesia
45. Faculty of Medicine, University of Indonesia
46. Narayana Nethralaya Eye Hospital, Bangalore, India.
47. Einhorn Clinical Research Center, New York Eye and Ear Infirmary of Mount Sinai, New York, New York, USA
48. Department of Ophthalmology, Kobe City Medical Center General Hospital, Kobe, Japan
49. Nepal Glaucoma Eye Clinic, Tilganga Institute of Ophthalmology, Kathmandu, Nepal
50. Department of Ophthalmology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
51. Oxford Eye Hospital, John Radcliffe Hospital, Oxford University Hospitals NHS Trust, Oxford, UK
52. Department of Ophthalmology, Konyang University, Kim’s Eye Hospital, Myung-Gok Eye Research Institute, Seoul, South Korea
53. Dipartimento di Scienze Chirurgiche, Universita’ di Torino, Turin, Italy.
54. Ozaki Eye Hospital, Hyuga, Japan
55. Department of Ophthalmology, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan
56. Department of Ophthalmology, The University of Hong Kong, Hong Kong, China
57. Department of Ophthalmology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
58. Department of Ophthalmology, No(1) Defence Services General Hospital, Yangon, Union of Myanmar
59. Mizoguchi Eye Hospital, Sasebo, Nagasaki, Japan
60. Department of Ophthalmology, Oita University Faculty of Medicine, Oita, Japan
61. Department of Ophthalmology, Yonsei University College of Medicine, Seoul, South Korea
62. Shijiazhuang First Eye Hospital, Shijiazhuang, Hebei Province, China
63. Handan Eye Hospital, Handan, Hebei Province, China
64. Eye Institute and Affiliated Xiamen Eye Center, Xiamen University, Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, Xiamen, Fujian, China
65. Anyang Eye Hospital, Anyang, Hebei Province, China
66. Department of Ophthalmology, Pasig City General Hospital, Pasig City, Philippines
67. University of Malaya, Eye Research Centre, Malaysia
68. Department of Ophthalmology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
69. Myanmar Eye Centre, Pun Hlaing Silom Hospital, Yangon, Union of Myanmar
70. Myanmar Eye Centre, Shwe La Min Hospital, Yangon, Union of Myanmar
71. Department of Ophthalmology/Glaucoma Section, Asian Hospital & Medical Center, Muntinlupa City, Philippines.
72. Binan Doctor's Eye Center, Binan Doctors' Hospital, Laguna, Philippines
73. University Hospital Nottingham, Dept of Ophthalmology, Univ of Nottingham, Nottingham, UK
74. The BMI Park Hospital Nottingham, Nottingham NG5 8RX, UK
75. International Specialist Eye Centre, Kuala Lumpur, Malaysia
76. Glaucoma Clinic, Aravind Eye Hospital, Pondicherry, Tamilnadu, India
77. Glaucoma Clinic, Aravind Eye Hospital, Madurai, Tamilnadu, India
78. Department of Ophthalmology, Faculty of Medical Sciences, University of Campinas, Campinas, SP, Brazil
79. Instituto de Ciencias Medicas, Lima –Perú
80. Hospital Nacional Arzobispo Loayza, Lima – Perú
81. Centro de Genetica y Biologia Molecular, Universidad de San Martin de Porres, Lima – Perú
82. Wilmer Eye Institute, Johns Hopkins Hospital School of Medicine, Baltimore, USA
83. Department of Human Genetics, Radboud University Medical Centre; Nijmegen, the Netherlands.
84. Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia
85. Centre for Eye Research Australia, University of Melbourne, Royal Victorian Eye and Ear Hospital, Melbourne, Victoria, Australia.
86. Department of Ophthalmology, King Chulalongkorn Memorial Hospital, Bangkok, Thailand
87. Department of Ophthalmology, Queen Mary Hospital, Hong Kong, China
88. Department of Ophthalmology, North Okkalarpa General Hospital, Yangon, Union of Myanmar
89. Institute for Human Genetics, University of California San Francisco, San Francisco, California 94143, USA
90. Oxford University Clinical Research Unit, Ho Chi Minh City, Viet Nam
91. Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Australia
92. Hospital for Tropical Diseases, Ho Chi Minh City, Viet Nam
93. Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, P. R. China.
94. Department of Experimental Research, Sun Yat-sen University Cancer Center, Guangzhou, P. R. China
95. Peking Union Medical College, Beijing, P. R. China
96. Oxford University Clinical Research Unit-Nepal, Patan Academy of Health Sciences, Patan Hospital, Patan, Nepal.
97. Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany
98. Department of Ophthalmology, Monfalcone Hospital, Gorizia, Italy
99. Department of Surgery, Section of Ophthalmology, University of Siena, Siena, Italy.
100. Centre for Vision Research, Department of Ophthalmology, Westmead Institute for Medical Research, University of Sydney, NSW, Australia
101. Department of Ophthalmology and Visual Sciences, Carver College of Medicine, University of Iowa.
102. The Wynn Institute for Vision Research, University of Iowa, USA
103. Department of Ophthalmology, Duke University Eye Center, Durham, NC, USA
104. Department of Medicine, Duke University Medical Center, Durham, NC, USA
105. Division of Medical Oncology, National Cancer Centre, Singapore
106. Department of Economics, National University of Singapore, Singapore
107. Department of Psychology, National University of Singapore, Singapore
108. Institut Pasteur, Functional Genetics of Infectious Diseases Unit, Department of Genomes and Genetics, Paris, 75015, France
109. Centre National de la Recherche Scientifique, Unité de Recherche Associée 3012, Paris, France
110. Department of Ophthalmology, Seoul National University Bundang Hospital, Gyeonggi, Korea
111. Department of Ophthalmology, Seoul Metropolitan Government Seoul National University Boramae Medical Center, Seoul, Korea
112. Department of Medical Microbiology and Virology, University Medical Center Utrecht, Utrecht 3584 CX, The Netherlands
113. GROW Research Lab, Narayana Nethralaya Foundation, Bangalore, India
114. Department of Biochemistry, Al-Nafees Medical College & Hospital, Isra University, Islamabad, Pakistan
115. Beijing Institute of Ophthalmology, Beijing Tongren Hospital, Capital Medical University, Beijing, China
116. Saw Swee Hock School of Public Health, National University of Singapore, Singapore.
117. Life Sciences Institute, National University of Singapore, Singapore.
118. NUS Graduate School for Integrative Science and Engineering, National University of Singapore, Singapore.
119. Department of Statistics and Applied Probability, National University of Singapore, Singapore.
120. Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
121. Department of Glaucoma, Institute of Ophthalmology "Conde de Valenciana", Mexico City, Mexico
122. Department of Genetics, Institute of Ophthalmology "Conde de Valenciana", Mexico City, Mexico
123. Department of Biochemistry, Faculty of Medicine, Universidad Nacional Autonoma de Mexico, Mexico City, Mexico
124. These authors contributed equally to this work
125. These authors jointly supervised this work
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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.
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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 220 staff, and more than 100 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 2,000 peer-reviewed papers supported by over S$200 million in competitive research grants. SERI has trained more than 150 current and past graduate students; and has been conferred over 350 national & international awards and 105 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.
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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.
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 Five of these eight genes are newly discovered by the GIS-SERI team, with the other three previously reported by the same group in 2012
 Quigley, H.A. & Broman, A.T. The number of people with glaucoma worldwide in 2010 and 2020. Br J Ophthalmol 90, 262-7 (2006)