Genome-wide association meta-analysis highlights light-induced signaling as a driver for refractive error

Refractive errors, including myopia, are the most frequent eye disorders worldwide and an increasingly common cause of blindness. This genome-wide association meta-analysis in 160,420 participants and replication in 95,505 participants increased the number of established independent signals from 37...

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Published in:Nature genetics Vol. 50; no. 6; pp. 834 - 848
Main Authors: Tedja, Milly S., Wojciechowski, Robert, Hysi, Pirro G., Eriksson, Nicholas, Furlotte, Nicholas A., Verhoeven, Virginie J. M., Iglesias, Adriana I., Meester-Smoor, Magda A., Tompson, Stuart W., Fan, Qiao, Khawaja, Anthony P., Cheng, Ching-Yu, Höhn, René, Yamashiro, Kenji, Wenocur, Adam, Grazal, Clare, Haller, Toomas, Metspalu, Andres, Wedenoja, Juho, Jonas, Jost B., Wang, Ya Xing, Xie, Jing, Mitchell, Paul, Foster, Paul J., Klein, Barbara E. K., Klein, Ronald, Paterson, Andrew D., Hosseini, S. Mohsen, Shah, Rupal L., Williams, Cathy, Teo, Yik Ying, Tham, Yih Chung, Gupta, Preeti, Zhao, Wanting, Shi, Yuan, Saw, Woei-Yuh, Tai, E-Shyong, Sim, Xue Ling, Huffman, Jennifer E., Polašek, Ozren, Hayward, Caroline, Bencic, Goran, Rudan, Igor, Wilson, James F., Joshi, Peter K., Tsujikawa, Akitaka, Matsuda, Fumihiko, Whisenhunt, Kristina N., Zeller, Tanja, van der Spek, Peter J., Haak, Roxanna, Meijers-Heijboer, Hanne, van Leeuwen, Elisabeth M., Iyengar, Sudha K., Lass, Jonathan H., Hofman, Albert, Rivadeneira, Fernando, Uitterlinden, André G., Vingerling, Johannes R., Lehtimäki, Terho, Raitakari, Olli T., Biino, Ginevra, Concas, Maria Pina, Schwantes-An, Tae-Hwi, Igo, Robert P., Cuellar-Partida, Gabriel, Martin, Nicholas G., Craig, Jamie E., Gharahkhani, Puya, Williams, Katie M., Nag, Abhishek, Rahi, Jugnoo S., Cumberland, Phillippa M., Delcourt, Cécile, Bellenguez, Céline, Ried, Janina S., Bergen, Arthur A., Meitinger, Thomas, Gieger, Christian, Wong, Tien Yin, Hewitt, Alex W., Mackey, David A., Simpson, Claire L., Pfeiffer, Norbert, Pärssinen, Olavi, Baird, Paul N., Vitart, Veronique, Amin, Najaf, van Duijn, Cornelia M., Bailey-Wilson, Joan E., Young, Terri L., Saw, Seang-Mei, Stambolian, Dwight, MacGregor, Stuart, Guggenheim, Jeremy A., Tung, Joyce Y., Hammond, Christopher J., Klaver, Caroline C. W.
Format: Journal Article
Language:English
Published: New York Nature Publishing Group US 01.06.2018
Nature Publishing Group
Subjects:
45/43
631/208/205/2138
692/308
692/699
Adult
Agriculture
Angiogenesis
Animal Genetics and Genomics
Asian People - genetics
Bioinformatics
Biomedical and Life Sciences
Biomedicine
Blindness
Blindness - genetics
Blindness - metabolism
Cancer Research
Consortia
Endothelium
Epithelium
Extracellular matrix
Eye
Eye disorders
Female
Gene Expression Regulation
Gene Function
Gene regulation
Genes
Genetic aspects
Genetic Predisposition to Disease
Genome-Wide Association Study - methods
Genomes
Human Genetics
Humans
Life Sciences
Male
Meta-analysis
Morphology
Myopia
Myopia - genetics
Neurotransmission
Polymorphism, Single Nucleotide
Post-transcription
Quality control
Refractive errors
Refractive Errors - genetics
Refractive Errors - metabolism
Retina
Retina - metabolism
Retinal cells
Retinal pigment epithelium
Retinal Pigment Epithelium - metabolism
Risk factors
Signal Transduction
Signaling
Studies
White People - genetics
United Kingdom > UK
ISSN:1061-4036, 1546-1718, 1546-1718
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Summary:Refractive errors, including myopia, are the most frequent eye disorders worldwide and an increasingly common cause of blindness. This genome-wide association meta-analysis in 160,420 participants and replication in 95,505 participants increased the number of established independent signals from 37 to 161 and showed high genetic correlation between Europeans and Asians (>0.78). Expression experiments and comprehensive in silico analyses identified retinal cell physiology and light processing as prominent mechanisms, and also identified functional contributions to refractive-error development in all cell types of the neurosensory retina, retinal pigment epithelium, vascular endothelium and extracellular matrix. Newly identified genes implicate novel mechanisms such as rod-and-cone bipolar synaptic neurotransmission, anterior-segment morphology and angiogenesis. Thirty-one loci resided in or near regions transcribing small RNAs, thus suggesting a role for post-transcriptional regulation. Our results support the notion that refractive errors are caused by a light-dependent retina-to-sclera signaling cascade and delineate potential pathobiological molecular drivers. Transancestral GWAS meta-analysis in 160,420 individuals identifies 139 loci associated with refractive error, including myopia. Newly identified genes implicate pathways involved in eye growth and light signaling cascades.
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21. MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
83. Retino Center, Singapore National Eye Centre, Singapore, Singapore.
59. Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany.
78. Department of Ophthalmology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
16. Université de Bordeaux, Inserm, Bordeaux Population Health Research Center, team LEHA, UMR 1219, F-33000 Bordeaux, France.
58. Department of Ophthalmology, Yokohama City University School of Medicine, Yokohama, Kanagawa, Japan.
27. Statistical Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
43. Beijing Institute of Ophthalmology, Beijing Key Laboratory of Ophthalmology and Visual Sciences, Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing, China.
41. Department of Ophthalmology and Visual Sciences, Case Western Reserve University and University Hospitals Eye Institute, Cleveland, Ohio, USA.
84. Centre for Myopia Research, School of Optometry, The Hong Kong Polytechnic University, Hong Kong, Hong Kong.
1. Singapore Eye Research Institute, Singapore National Eye Centre, Singapore.
15. Department of Ophthalmology and Visual Sciences, John Moran Eye Center, University of Utah, Salt Lake City, Utah, USA.
74. Department of Genetics, Genomics and Informatics, University of Tennessee Health Sciences Center, Memphis, Tenessee.
24. Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, Ohio, USA.
40. School of Social and Community Medicine, University of Bristol, Bristol, UK.
82. Academic Medicine Research Institute, Singapore.
51. Department of Ophthalmology and Visual Sciences, University of Wisconsin–Madison, Madison, Wisconsin, USA.
45. Department of Public Health, University of Helsinki, Helsinki, Finland.
48. Saw Swee Hock School of Public Health, National University Health Systems, National University of Singapore, Singapore.
18. Institute of Genetic Epidemiology, Helmholtz Zentrum München—German Research Center for Environmental Health, Neuherberg, Germany.
5. Duke-NUS Medical School, Singapore, Singapore.
11. Ocular Epidemiology Research Group, Singapore Eye Research Institute, Singapore National Eye Centre, Singapore.
17. State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China.
42. Department of Ophthalmology, Medical Faculty Mannheim of the Ruprecht-Karls-University of Heidelberg, Mannheim, Germany.
67. Faculty of Medicine, University of Split, Split, Croatia.
Members of the 23andMe Research Team: Michelle Agee, Babak Alipanahi, Adam Auton, Robert K. Bell, Katarzyna Bryc, Sarah L. Elson, Pierre Fontanillas, David A. Hinds, Jennifer C. McCreight, Karen E. Huber, Aaron Kleinman, Nadia K. Litterman, Matthew H. McIntyre, Joanna L. Mountain, Elizabeth S. Noblin, Carrie A.M. Northover, Steven J. Pitts, J. Fah Sathirapongsasuti, Olga V. Sazonova, Janie F. Shelton, Suyash Shringarpure, Chao Tian, Vladimir Vacic, Catherine H. Wilson.
13. Department of Genetics, Case Western Reserve University, Cleveland, Ohio, USA.
25. University Hospital ‘San Giovanni di Dio’, Cagliari, Italy.
77. MRC Epidemiology Unit, Institute of Metabolic Sciences, University of Cambridge, Cambridge, UK.
35. Department of Ophthalmology, Menzies Institute of Medical Research, University of Tasmania, Hobart, Australia.
70. Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland.
52. MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London, UK.
31. Department of Statistical Science, School of Mathematics, Sun Yat-Sen University, Guangzhou, China.
The CREAM Consortium
Affiliations
14. Great Ormond Street Institute of Child Health, University College London, London, UK.
49. Division of Human Genetics, Genome Institute of Singapore, Singapore.
79. Department of Population Health Sciences, Bristol Medical School, Bristol, UK.
80. Department of Epidemiology and Medicine, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.
73. Max Planck Institute for Psycholinguistics, Nijmegen, The Netherlands.
8. Centre for Global Health Research, Usher Institute for Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, UK.
46. Institute for Molecular Medicine Finland FIMM, HiLIFE Unit, University of Helsinki, Helsinki, Finland.
26. NIHR Biomedical Research Centre, Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, London, UK.
61. Department of Ophthalmology, Centre for Vision Research, Westmead Institute for Medical Research, University of Sydney, Sydney, Australia.
These authors contributed equally to this work.
85. Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Hong Kong, Hong Kong.
34. MRC Human Genetics Unit, MRC Institute of Genetics & Molecular Medicine, University of Edinburgh, Edinburgh, UK.
20. Translational Research Institute, University of Queensland Diamantina Institute, Brisbane, Queensland, Australia.
These authors jointly directed this work.
72. Department of Ophthalmology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
68. Ulverscroft Vision Research Group, University College London, London, UK.
33. Section of Academic Ophthalmology, School of Life Course Sciences, King’s College London, London, UK.
66. Institute of Genetic and Biomedic Research, National Research Council, Cagliari, Italy.
2. Department of Ophthalmology, National University Health Systems, National University of Singapore, Singapore.
3. Computational and Statistical Genomics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.
19. Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.
30. School of Optometry & Vision Sciences, Cardiff University, Cardiff, UK.
Tin Aung1,2, Joan E. Bailey-Wilson3, Paul Nigel Baird4, Amutha Barathi Veluchamy1,5, Ginevra Biino6, Kathryn P. Burdon7, Harry Campbell8, Li Jia Chen9, Peng Chen2, Wei Chen10, Ching-Yu Cheng11,12, Emily Chew13, Jamie E. Craig7, Phillippa M. Cumberland14, Margaret M. Deangelis15, Cécile Delcourt16, Xiaohu Ding17, Angela Döring18, Cornelia M. van Duijn19, David M. Evans20,21, Qiao Fan12, Lindsay Farrer15, Sheng Feng22, Brian Fleck23, Rhys D. Fogarty7, Jeremy R. Fondran24, Maurizio Fossarello25, Paul J. Foster26, Puya Gharahkhani27, Christian Gieger18, Adriana I. Iglesias19,28,29, Jeremy A. Guggenheim30, Xiaobo Guo17,31, Toomas Haller32, Christopher J. Hammond33, Caroline Hayward34, Mingguang He4,17, Alex W. Hewitt4,35,36, René Höhn37,38, S. Mohsen Hosseini39, Laura D. Howe21,40, Pirro G. Hysi33, Robert P. Igo Jr.24, Sudha K. Iyengar13,24,41, Sarayut Janmahasatian24, Vishal Jhanji9, Jost B. Jonas42,43, Mika Kähönen44, Jaakko Kaprio45,46, John P. Kemp21, Kay-Tee Khaw47, Anthony P. Khawaja26,47, Chiea-Chuen Khor2,15,48,49, Caroline C. W. Klaver19,29,50, Barbara E. Klein51, Ronald Klein51, Eva Krapohl52, Jean-François Korobelnik53,54, Jonathan H. Lass24,41, Kris Lee51, Elisabeth M. van Leeuwen19,29, Terho Lehtimäki55,56, Shi-Ming Li43, Yi Lu27, Robert N. Luben47, Stuart MacGregor27, David A. Mackey4,35,36, Kari-Matti Mäkelä55, Nicholas G. Martin57, George McMahon21, Akira Meguro58, Thomas Meitinger59,60, Andres Metspalu32, Evelin Mihailov32, Paul Mitchell61, Masahiro Miyake62, Nobuhisa Mizuki58, Margaux Morrison15, Vinay Nangia63, Songhomitra Panda-Jonas63, Chi Pui Pang9, Olavi Pärssinen64,65, Andrew D. Paterson39, Norbert Pfeiffer38, Mario Pirastu66, Robert Plomin52, Ozren Polasek8,67, Jugnoo S. Rahi14,26,68, Olli Raitakari69,70, Taina Rantanen65, Janina S. Ried18, Igor Rudan8, Seang-Mei Saw48,71, Maria Schache4, Ilkka Seppälä55, Rupal L. Shah30, George Davey Smith21, Dwight Stambolian72, Beate St Pourcain21,73, Claire L. Simpson3,74, E-Shyong Tai48, Pancy O. Tam9, Milly S. Tedja19,29, Yik-Ying Teo48,75, J. Willem L. Tideman19,29, Nicholas J. Timpson21, Simona Vaccargiu66, Zoran Vatavuk76, Virginie J.M. Verhoeven19,28,29, Veronique Vitart34, Jie Jin Wang4,61, Ningli Wang43, Nick J. Wareham77, Juho Wedenoja45,78, Cathy Williams79, Katie M. Williams33, James F. Wilson8,34, Robert Wojciechowski3,80,81, Ya Xing Wang43, Tien-Yin Wong82,83, Alan F. Wright34, Jing Xie4, Liang Xu43, Kenji Yamashiro62, Maurice K.H. Yap84, Seyhan Yazar36, Shea Ping Yip85, Nagahisa Yoshimura62, Alvin L. Young9, Terri L. Young51, Jing Hua Zhao77, Wanting Zhao12,86, Xiangtian Zhou10
71. Myopia Research Group, Singapore Eye Research Institute, Singapore National Eye Centre, Singapore.
55. Department of Clinical Chemistry, Finnish Cardiovascular Research Center-Tampere, Faculty of Medicine and Life Sciences, University of Tampere.
64. Department of Ophthalmology, Central Hospital of Central Finland, Jyväskylä, Finland.
81. Wilmer Eye Institute, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA.
63. Suraj Eye Institute, Nagpur, Maharashtra, India.
6. Institute of Molecular Genetics, National Research Council of Italy, Sassari, Italy.
60. Institute of Human Genetics, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
A full list of CREAM consortium members appears at the end of the paper.
44. Department of Clinical Physiology, Tampere University Hospital and School of Medicine, University of Tampere, Tampere, Finland.
62. Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Kyoto, Japan.
56. Department of Clinical Chemistry, Fimlab Laboratories, University of Tampere, Tampere, Finland.
23. Princess Alexandra Eye Pavilion, Edinburgh, UK.
65. Gerontology Research Center, Faculty of Sport and Health Sciences, University of Jyväskylä, Jyväskylä, Finland.
10. School of Ophthalmology and Optometry, Eye Hospital, Wenzhou Medical University, China.
76. Department of Ophthalmology, Sisters of Mercy University Hospital, Zagreb, Croatia.
69. Resear
ISSN:1061-4036
1546-1718
1546-1718
DOI:10.1038/s41588-018-0127-7