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.
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We gratefully thank all study participants, their relatives and the staff at the recruitment centers for their invaluable contributions. We thank all contributors to the CREAM Consortium, 23andMe and UKEV for their generosity in sharing data and help in the production of this publication. Funding for this particular GWAS mega-analysis was provided by the European Research Council (ERC) under the European Union’s Horizon 2020 Research and Innovation Programme (grant 648268), the Netherlands Organisation for Scientific Research (NWO, grant 91815655) and the National Eye Institute (grant R01EY020483). Funding agencies that facilitated the execution of the individual studies are acknowledged in the Supplementary Note.
The Consortium for Refractive Error and Myopia (CREAM Consortium):
Tin Aung82,83, Amutha B. Veluchamy82,84, Kathryn P. Burdon58, Harry Campbell36, Li Jia Chen85, Peng Chen83, Wei Chen86, Emily Chew45, Margaret M. Deangelis87, Xiaohu Ding88, Angela Döring66, David M. Evans89,90, Sheng Feng91, Brian Fleck92, Rhys D. Fogarty58, Jeremy R. Fondran43, Maurizio Fossarello93, Xiaobo Guo88,94, Annet E. G. Haarman1,2, Mingguang He23,88, Laura D. Howe90,95, Sarayut Janmahasatian43, Vishal Jhanji85, Mika Kähönen96, Jaakko Kaprio20,97, John P. Kemp90, Kay-Tee Khaw11, Chiea-Chuen Khor29,83,87,98, Eva Krapohl99, Jean-François Korobelnik100,101, Kris Lee9, Shi-Ming Li22, Yi Lu56, Robert N. Luben11, Kari-Matti Mäkelä49, George McMahon90, Akira Meguro102, Evelin Mihailov18, Masahiro Miyake16, Nobuhisa Mizuki102, Margaux Morrison87, Vinay Nangia103, Konrad Oexle104, Songhomitra Panda-Jonas103, Chi Pui Pang85, Mario Pirastu105, Robert Plomin99, Taina Rantanen77, Maria Schache23, Ilkka Seppälä49, George D. Smith90, Beate St Pourcain90,106, Pancy O. Tam85, J. Willem L. Tideman1,2, Nicholas J. Timpson90, Simona Vaccargiu105, Zoran Vatavuk35, Jie Jin Wang23,24, Ningli Wang22, Nick J. Wareham107, Alan F. Wright33, Liang Xu22, Maurice K. H. Yap108, Seyhan Yazar74, Shea Ping Yip109, Nagahisa Yoshimura16, Alvin L. Young9, Jing Hua Zhao107 and Xiangtian Zhou86 UK Biobank Eye and Vision Consortium: Tariq M. Aslam110, Sarah A. Barman111, Jenny H. Barrett112, Paul N. Bishop110, Peter Blows12, Catey Bunce113, Roxana O. Carare114, Usha Chakravarthy115, Michelle Chan12, Sharon Chua12, David Crabb116, Alexander Day12, Parul Desai12, Bal Dhillon117, Andrew D. Dick118, Cathy A. Egan12, Sarah Ennis114, Marcus Fruttiger12, John Gallacher119, David F. Garway-Heath12, Jane Gibson114, Dan M. Gore12, Alison Hardcastle12, Simon P. Harding120, Ruth E. Hogg121, Pearse A. Keane12, Peng Tee Khaw12, Gerassimos Lascaratos12, Andrew Lotery122, Phil J. Luthert12, Tom J. MacGillivray123, Sarah L. Mackie124, Keith R. Martin125, Michelle McGaughey126, Bernadette McGuinness126, Gareth J. McKay126, Martin McKibbin127, Danny Mitry12, Tony Moore12, James E. Morgan26, Zaynah A. Muthy12, Eoin O’Sullivan128, Chris Owen129, Praveen J. Patel12, Euan N. Paterson126, Tunde Peto115, Axel Petzold130, Alicja R. Rudnicka129, Jay E. Self122,131, Sobha Sivaprasad12, David H. W. Steel132, Irene M. Stratton133, Nicholas Strouthidis12,Cathie L. M. Sudlow134, Caroline Thaung12, Dhanes Thomas12, Emanuele Trucco135, Adnan Tufail12, Stephen A. Vernon136, Ananth C. Viswanathan12, Jayne V. Woodside126, Max Yates137, Jennifer L. Y. Yip11 and Yalin Zheng120 23andMe Research Team: Michelle Agee7, Babak Alipanahi7, Adam Auton7, Robert K. Bell7, Katarzyna Bryc7, Sarah L. Elson7, Pierre Fontanillas7, David A. Hinds7, Jennifer C. McCreight7, Karen E. Huber7, Aaron Kleinman7, Nadia K. Litterman7, Matthew H. McIntyre7, Joanna L. Mountain7, Elizabeth S. Noblin7, Carrie A. M. Northover7, Steven J. Pitts7, J. Fah Sathirapongsasuti7, Olga V. Sazonova7, Janie F. Shelton7, Suyash Shringarpure7, Chao Tian7, Vladimir Vacic7 and Catherine H. Wilson7
N.A.F., N.E., J.Y.T. and the 23andMe Research Team are current or former employees of 23andMe, Inc., and hold stock or stock options in 23andMe. J.B.J. is a patent holder with Biocompatibles UK Ltd. (Franham, Surrey, UK) (Title: Treatment of eye diseases using encapsulated cells encoding and secreting neuroprotective factor and /or anti-angiogenic factor; international patent no. 20120263794) and is included in a patent application with University of Heidelberg (Heidelberg, Germany) (Title: Agents for use in the therapeutic or prophylactic treatment of myopia or hyperopia; European patent no. 3 070 101). The other authors declare no competing financial interests.
Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Figures 1–12, Supplementary Note and Supplementary Tables 1, 5–9, 12 and 17
Stage 1 - 3 Meta-Analyses and Conditional Analysis
Stage 3 Index Variants of FE and RE analyses
HWE p-value per cohort TopSNPs Stage 3
DEPICT analysis - gene-set enrichment
Ranking of associated genes according to biological plausibility
Genes with Human Ocular Phenotypes
Genes with Mice Ocular Phenotypes
Expression of Candidate Genes in Ocular Tissues
Genetic variants harboring known drug targets
Locus Zoom Plots
Forest Plots Stage 3 and Conditional Loci
Summary Statistics Stage 3 Meta-analysis
The CREAM Consortium
Tin Aung82,83, Amutha B. Veluchamy82, 84, Kathryn P. Burdon58, Harry Campbell36, Li Jia Chen85, Peng Chen83, Wei Chen86, Emily Chew45, Margaret M. Deangelis87, Xiaohu Ding88, Angela Döring66, David M. Evans89, 90, Sheng Feng91, Brian Fleck92, Rhys D. Fogarty58, Jeremy R. Fondran43, Maurizio Fossarello93, Xiaobo Guo88, 94, Annet E. G. Haarman1, 2, Mingguang He23, 88, Laura D. Howe90, 95, Sarayut Janmahasatian43, Vishal Jhanji85, Mika Kähönen96, Jaakko Kaprio20, 97, John P. Kemp90, Kay-Tee Khaw11, Chiea-Chuen Khor29, 83, 87, 98, Eva Krapohl99, Jean-François Korobelnik100, 101, Kris Lee9, Shi-Ming Li22, Yi Lu56, Robert N. Luben11, Kari-Matti Mäkelä49, George McMahon90, Akira Meguro102, Evelin Mihailov18, Masahiro Miyake16, Nobuhisa Mizuki102, Margaux Morrison87, Vinay Nangia103, Konrad Oexle104, Songhomitra Panda-Jonas103, Chi Pui Pang85, Mario Pirastu105, Robert Plomin99, Taina Rantanen77, Maria Schache23, Ilkka Seppälä49, George D. Smith90, Beate St Pourcain90, 106, Pancy O. Tam85, J. Willem L. Tideman1, 2, Nicholas J. Timpson90, Simona Vaccargiu105, Zoran Vatavuk35, Jie Jin Wang23, 24, Ningli Wang22, Nick J. Wareham107, Alan F. Wright33, Liang Xu22, Maurice K. H. Yap108, Seyhan Yazar74, Shea Ping Yip109, Nagahisa Yoshimura16, Alvin L. Young9, Jing Hua Zhao107 and Xiangtian Zhou86
23andMe Research Team
Michelle Agee7, Babak Alipanahi7, Adam Auton7, Robert K. Bell7, Katarzyna Bryc7, Sarah L. Elson7, Pierre Fontanillas7, David A. Hinds7, Jennifer C. McCreight7, Karen E. Huber7, Aaron Kleinman7, Nadia K. Litterman7, Matthew H. McIntyre7, Joanna L. Mountain7, Elizabeth S. Noblin7, Carrie A. M. Northover7, Steven J. Pitts7, J. Fah Sathirapongsasuti7, Olga V. Sazonova7, Janie F. Shelton7, Suyash Shringarpure7, Chao Tian7, Vladimir Vacic7 and Catherine H. Wilson7
UK Biobank Eye and Vision Consortium
Tariq M. Aslam110, Sarah A. Barman111, Jenny H. Barrett112, Paul N. Bishop110, Peter Blows12, Catey Bunce113, Roxana O. Carare114, Usha Chakravarthy115, Michelle Chan12, Sharon Chua12, David Crabb116, Alexander Day12, Parul Desai12, Bal Dhillon117, Andrew D. Dick118, Cathy A. Egan12, Sarah Ennis114, Marcus Fruttiger12, John Gallacher119, David F. Garway-Heath12, Jane Gibson114, Dan M. Gore12, Alison Hardcastle12, Simon P. Harding120, Ruth E. Hogg121, Pearse A. Keane12, Peng Tee Khaw12, Gerassimos Lascaratos12, Andrew Lotery122, Phil J. Luthert12, Tom J. MacGillivray123, Sarah L. Mackie124, Keith R. Martin125, Michelle McGaughey126, Bernadette McGuinness126, Gareth J. McKay126, Martin McKibbin127, Danny Mitry12, Tony Moore12, James E. Morgan26, Zaynah A. Muthy12, Eoin O’Sullivan128, Chris Owen129, Praveen J. Patel12, Euan N. Paterson126, Tunde Peto115, Axel Petzold130, Alicja R. Rudnicka129, Jay E. Self122,131, Sobha Sivaprasad12, David H. W. Steel132, Irene M. Stratton133, Nicholas Strouthidis12, Cathie L. M. Sudlow134, Caroline Thaung12, Dhanes Thomas12, Emanuele Trucco135, Adnan Tufail12, Stephen A. Vernon136, Ananth C. Viswanathan12, Jayne V. Woodside126, Max Yates137, Jennifer L. Y. Yip11 and Yalin Zheng120
82Singapore Eye Research Institute, Singapore National Eye Centre, Singapore, Singapore. 83Department of Ophthalmology, National University HealthSystems, National University of Singapore, Singapore, Singapore. 84Duke-NUS Medical School, Singapore, Singapore, Singapore. 85Department ofOphthalmology and Visual Sciences, Chinese University of Hong Kong, Hong Kong Eye Hospital, Kowloon, Hong Kong. 86School of Ophthalmologyand Optometry, Eye Hospital, Wenzhou Medical University, Wenzhou, China. 87Department of Ophthalmology and Visual Sciences, John Moran EyeCenter, University of Utah, Salt Lake City, UT, USA. 88State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University,Guangzhou, China. 89Translational Research Institute, University of Queensland Diamantina Institute, Brisbane, Queensland, Australia. 90MRC IntegrativeEpidemiology Unit, University of Bristol, Bristol, UK. 91Department of Pediatric Ophthalmology, Duke Eye Center For Human Genetics, Durham, NC, USA. 92Princess Alexandra Eye Pavilion, Edinburgh, UK. 93University Hospital ‘San Giovanni di Dio’, Cagliari, Italy. 94Department of Statistical Science, Schoolof Mathematics, Sun Yat-Sen University, Guangzhou, China. 95School of Social and Community Medicine, University of Bristol, Bristol, UK. 96Departmentof Clinical Physiology, Tampere University Hospital and School of Medicine, University of Tampere, Tampere, Finland. 97Institute for Molecular MedicineFinland FIMM, HiLIFE Unit, University of Helsinki, Helsinki, Finland. 98Division of Human Genetics, Genome Institute of Singapore, Singapore, Singapore. 99MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London, UK. 100Université de Bordeaux, Bordeaux, France. 101Institut National de la Santé Et de la Recherche Médicale (INSERM), Institut de Santé Publiqued’Épidémiologie et de Développement (ISPED), Centre INSERM U897–Epidemiologie-Biostatistique, Bordeaux, France. 102Department of Ophthalmology, Yokohama City University School of Medicine, Yokohama, Japan. 103Suraj Eye Institute, Nagpur, Maharashtra, India. 104Institute of Neurogenomics, Helmholtz Zentrum München, German Research Centre for Environmental Health, Neuherberg, Germany. 105Institute of Genetic and Biomedic Research, National Research Council, Cagliari, Italy. 106Max Planck Institute for Psycholinguistics, Nijmegen, The Netherlands. 107MRC Epidemiology Unit, Instituteof Metabolic Sciences, University of Cambridge, Cambridge, UK. 108Centre for Myopia Research, School of Optometry, Hong Kong Polytechnic University, Hong Kong, Hong Kong. 109Department of Health Technology and Informatics, Hong Kong Polytechnic University, Hong Kong, Hong Kong. 110ManchesterRoyal Eye Hospital, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK. 111School of ComputerScience and Mathematics, Kingston University, Surrey, UK. 112Section of Epidemiology and Biostatistics, Leeds Institute of Cancer and Pathology, Universityof Leeds, Leeds, UK. 113Primary Care & Public Health Sciences, King’s College London, London, UK. 114Faculty of Medicine University of Southampton, Southampton General Hospital, Southampton, UK. 115School of Medicine, Dentistry and Biomedical Sciences, Queen’s University Belfast, Belfast, NorthernIreland, UK. 116Optometry and Visual Science, School of Health Science, City, University of London, London, UK. 117Division of Health Sciences & Centrefor Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK. 118School of Clinical Sciences, Faculty of Medicine and Dentistry, University of Bristol,Bristol, UK. 119Department of Psychiatry, Oxford University, Warneford Hospital, Oxford, UK. 120Department of Eye and Vision Science, University ofLiverpool, Liverpool, UK. 121Centre for Experimental Medicine, Queen’s University Belfast, Belfast, Northern Ireland, UK. 122Department of Ophthalmology, University of Southampton NHS Foundation Trust, Southampton, UK. 123Edinburgh Imaging, University of Edinburgh, Edinburgh, UK. 124Leeds Instituteof Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, UK. 125Department of Ophthalmology, Cambridge University Hospitals NHSFoundation Trust, Cambridge, UK. 126Centre for Public Health, Queen’s University Belfast, Belfast, Northern Ireland, UK. 127Department of Ophthalmology,Leeds Teaching Hospitals NHS Trust, Leeds, UK. 128Department of Ophthalmology, King’s College Hospital NHS Foundation Trust, London, UK. 129StGeorge’s, University of London, London, UK. 130UCL Institute of Neurology, London, UK. 131Clinical and Experimental Sciences, Faculty of Medicine,University of Southampton, Southampton, UK. 132Institute of Genetic Medicine, Newcastle University, Newcastle Upon Tyne, UK. 133Gloucestershire RetinalResearch Group, Gloucestershire Hospitals NHS Foundation Trust, Cheltenham General Hospital, Cheltenham, UK. 134Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK. 135School of Science and Engineering, University of Dundee, Dundee, UK. 136Nottingham University Hospitals NHSTrust, Nottingham, UK. 137Norwich Medical School, University of East Anglia, Norwich, Norfolk, UK.
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Tedja, M.S., Wojciechowski, R., Hysi, P.G. et al. Genome-wide association meta-analysis highlights light-induced signaling as a driver for refractive error. Nat Genet 50, 834–848 (2018). https://doi.org/10.1038/s41588-018-0127-7
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