Article | Published:

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

Nature Geneticsvolume 50pages834848 (2018) | Download Citation

Abstract

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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Acknowledgements

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

Author information

Author notes

  1. These authors contributed equally: Milly S. Tedja, Robert Wojciechowski, Pirro G. Hysi, Nicholas Eriksson, Nicholas A. Furlotte, Virginie J. M. Verhoeven

  2. These authors jointly supervised this work: Jeremy A. Guggenheim, Joyce Y. Tung, Christopher J. Hammond, Caroline C. W. Klaver.

  3. A list of members and affiliations appears at the end of the paper.

Affiliations

  1. Department of Ophthalmology, Erasmus Medical Center, Rotterdam, The Netherlands

    • Milly S. Tedja
    • , Virginie J. M. Verhoeven
    • , Adriana I. Iglesias
    • , Magda A. Meester-Smoor
    • , Annet E. G. Haarman
    • , J. Willem L. Tideman
    • , Elisabeth M. van Leeuwen
    • , Johannes R. Vingerling
    •  & Caroline C. W. Klaver
  2. Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands

    • Milly S. Tedja
    • , Virginie J. M. Verhoeven
    • , Adriana I. Iglesias
    • , Magda A. Meester-Smoor
    • , Annet E. G. Haarman
    • , J. Willem L. Tideman
    • , Elisabeth M. van Leeuwen
    • , Albert Hofman
    • , Fernando Rivadeneira
    • , André G. Uitterlinden
    • , Najaf Amin
    • , Cornelia M. van Duijn
    •  & Caroline C. W. Klaver
  3. Department of Epidemiology and Medicine, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA

    • Robert Wojciechowski
  4. Computational and Statistical Genomics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA

    • Robert Wojciechowski
    • , Tae-Hwi Schwantes-An
    • , Claire L. Simpson
    •  & Joan E. Bailey-Wilson
  5. Wilmer Eye Institute, Johns Hopkins Medical Institutions, Baltimore, MD, USA

    • Robert Wojciechowski
  6. Section of Academic Ophthalmology, School of Life Course Sciences, King’s College London, London, UK

    • Pirro G. Hysi
    • , Katie M. Williams
    •  & Christopher J. Hammond
  7. 23andMe, Inc., Mountain View, CA, USA

    • Nicholas Eriksson
    • , Nicholas A. Furlotte
    • , 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
    •  & Joyce Y. Tung
  8. Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands

    • Virginie J. M. Verhoeven
    •  & Adriana I. Iglesias
  9. Department of Ophthalmology and Visual Sciences, University of Wisconsin–Madison, Madison, WI, USA

    • Stuart W. Tompson
    • , Barbara E. K. Klein
    • , Ronald Klein
    • , Kris Lee
    • , Alvin L. Young
    • , Kristina N. Whisenhunt
    •  & Terri L. Young
  10. Centre for Quantitative Medicine, DUKE–National University of Singapore, Singapore, Singapore

    • Qiao Fan
    • , Ching-Yu Cheng
    •  & Wanting Zhao
  11. Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK

    • Anthony P. Khawaja
    • , Kay-Tee Khaw
    • , Robert N. Luben
    •  & Jennifer L. Y. Yip
  12. NIHR Biomedical Research Centre, Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, London, UK

    • Anthony P. Khawaja
    • , Paul J. Foster
    • , Peter Blows
    • , Michelle Chan
    • , Sharon Chua
    • , Alexander Day
    • , Parul Desai
    • , Cathy A. Egan
    • , Marcus Fruttiger
    • , David F. Garway-Heath
    • , Dan M. Gore
    • , Alison Hardcastle
    • , Pearse A. Keane
    • , Peng Tee Khaw
    • , Gerassimos Lascaratos
    • , Phil J. Luthert
    • , Danny Mitry
    • , Tony Moore
    • , Zaynah A. Muthy
    • , Praveen J. Patel
    • , Sobha Sivaprasad
    • , Nicholas Strouthidis
    • , Caroline Thaung
    • , Dhanes Thomas
    • , Adnan Tufail
    • , Ananth C. Viswanathan
    •  & Jugnoo S. Rahi
  13. Ocular Epidemiology Research Group, Singapore Eye Research Institute, Singapore National Eye Centre, Singapore, Singapore

    • Ching-Yu Cheng
    •  & Yih Chung Tham
  14. Department of Ophthalmology, University Hospital Bern, Inselspital, University of Bern, Bern, Switzerland

    • René Höhn
  15. Department of Ophthalmology, University Medical Center Mainz, Mainz, Germany

    • René Höhn
    •  & Norbert Pfeiffer
  16. Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Kyoto, Japan

    • Kenji Yamashiro
    • , Masahiro Miyake
    • , Nagahisa Yoshimura
    •  & Akitaka Tsujikawa
  17. Department of Ophthalmology, University of Pennsylvania, Philadelphia, PA, USA

    • Adam Wenocur
    • , Clare Grazal
    •  & Dwight Stambolian
  18. Estonian Genome Center, University of Tartu, Tartu, Estonia

    • Toomas Haller
    • , Andres Metspalu
    •  & Evelin Mihailov
  19. Department of Ophthalmology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland

    • Juho Wedenoja
  20. Department of Public Health, University of Helsinki, Helsinki, Finland

    • Juho Wedenoja
    •  & Jaakko Kaprio
  21. Department of Ophthalmology, Medical Faculty Mannheim of the Ruprecht-Karls-University of Heidelberg, Mannheim, Germany

    • Jost B. Jonas
  22. Beijing Institute of Ophthalmology, Beijing Key Laboratory of Ophthalmology and Visual Sciences, Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing, China

    • Jost B. Jonas
    • , Ya Xing Wang
    • , Shi-Ming Li
    • , Ningli Wang
    •  & Liang Xu
  23. Centre for Eye Research Australia, Ophthalmology, Department of Surgery, University of Melbourne, Royal Victorian Eye and Ear Hospital, Melbourne, Victoria, Australia

    • Jing Xie
    • , Mingguang He
    • , Maria Schache
    • , Jie Jin Wang
    • , Alex W. Hewitt
    • , David A. Mackey
    •  & Paul N. Baird
  24. Department of Ophthalmology, Centre for Vision Research, Westmead Institute for Medical Research, University of Sydney, Sydney, New South Wales, Australia

    • Paul Mitchell
    •  & Jie Jin Wang
  25. Program in Genetics and Genome Biology, Hospital for Sick Children and University of Toronto, Toronto, Ontario, Canada

    • Andrew D. Paterson
    •  & S. Mohsen Hosseini
  26. School of Optometry & Vision Sciences, Cardiff University, Cardiff, UK

    • Rupal L. Shah
    • , James E. Morgan
    •  & Jeremy A. Guggenheim
  27. Department of Population Health Sciences, Bristol Medical School, Bristol, UK

    • Cathy Williams
  28. Department of Statistics and Applied Probability, National University of Singapore, Singapore, Singapore

    • Yik Ying Teo
  29. Saw Swee Hock School of Public Health, National University Health Systems, National University of Singapore, Singapore, Singapore

    • Yik Ying Teo
    • , E-Shyong Tai
    • , Xue Ling Sim
    • , Chiea-Chuen Khor
    •  & Seang-Mei Saw
  30. Department of Health Service Research, Singapore Eye Research Institute, Singapore National Eye Centre, Singapore, Singapore

    • Preeti Gupta
  31. Statistics Support Platform, Singapore Eye Research Institute, Singapore National Eye Centre, Singapore, Singapore

    • Wanting Zhao
    •  & Yuan Shi
  32. Life Sciences Institute, National University of Singapore, Singapore, Singapore

    • Woei-Yuh Saw
  33. MRC Human Genetics Unit, MRC Institute of Genetics & Molecular Medicine, University of Edinburgh, Edinburgh, UK

    • Jennifer E. Huffman
    • , Caroline Hayward
    • , James F. Wilson
    • , Alan F. Wright
    •  & Veronique Vitart
  34. Faculty of Medicine, University of Split, Split, Croatia

    • Ozren Polašek
  35. Department of Ophthalmology, Sisters of Mercy University Hospital, Zagreb, Croatia

    • Goran Bencic
    •  & Zoran Vatavuk
  36. Centre for Global Health Research, Usher Institute for Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, UK

    • Igor Rudan
    • , James F. Wilson
    • , Harry Campbell
    •  & Peter K. Joshi
  37. Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan

    • Fumihiko Matsuda
  38. Clinic for General and Interventional Cardiology, University Heart Center Hamburg, Hamburg, Germany

    • Tanja Zeller
  39. Department of Bioinformatics, Erasmus Medical Center, Rotterdam, The Netherlands

    • Peter J. van der Spek
    •  & Roxanna Haak
  40. Department of Clinical Genetics, Academic Medical Center, Amsterdam, The Netherlands

    • Hanne Meijers-Heijboer
    •  & Arthur A. Bergen
  41. Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands

    • Hanne Meijers-Heijboer
  42. Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH, USA

    • Jeremy R. Fondran
    • , Sarayut Janmahasatian
    • , Sudha K. Iyengar
    • , Jonathan H. Lass
    •  & Robert P. Igo Jr
  43. Department of Ophthalmology and Visual Sciences, Case Western Reserve University and University Hospitals Eye Institute, Cleveland, OH, USA

    • Sudha K. Iyengar
    •  & Jonathan H. Lass
  44. Department of Genetics, Case Western Reserve University, Cleveland, OH, USA

    • Emily Chew
    •  & Sudha K. Iyengar
  45. Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA

    • Albert Hofman
  46. Netherlands Consortium for Healthy Ageing, Netherlands Genomics Initiative, The Hague, The Netherlands

    • Albert Hofman
    • , Fernando Rivadeneira
    •  & André G. Uitterlinden
  47. Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands

    • Fernando Rivadeneira
    •  & André G. Uitterlinden
  48. Department of Clinical Chemistry, Finnish Cardiovascular Research Center–Tampere, Faculty of Medicine and Life Sciences, University of Tampere, Tampere, Finland

    • Kari-Matti Mäkelä
    • , Ilkka Seppälä
    •  & Terho Lehtimäki
  49. Department of Clinical Chemistry, Fimlab Laboratories, University of Tampere, Tampere, Finland

    • Terho Lehtimäki
  50. Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland

    • Olli T. Raitakari
  51. Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland

    • Olli T. Raitakari
  52. Institute of Molecular Genetics, National Research Council of Italy, Pavia, Italy

    • Ginevra Biino
  53. Institute for Maternal and Child Health–IRCCS ‘Burlo Garofolo’, Trieste, Italy

    • Maria Pina Concas
  54. Department of Medical and Molecular Genetics, Indiana University, School of Medicine, Indianapolis, IN, USA

    • Tae-Hwi Schwantes-An
  55. Statistical Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia

    • Yi Lu
    • , Gabriel Cuellar-Partida
    • , Puya Gharahkhani
    •  & Stuart MacGregor
  56. Genetic Epidemiology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia

    • Nicholas G. Martin
  57. Department of Ophthalmology, Flinders University, Adelaide, South Australia, Australia

    • Kathryn P. Burdon
    • , Rhys D. Fogarty
    •  & Jamie E. Craig
  58. Department of Twin Research and Genetic Epidemiology, King’s College London, London, UK

    • Abhishek Nag
  59. Great Ormond Street Institute of Child Health, University College London, London, UK

    • Jugnoo S. Rahi
    •  & Phillippa M. Cumberland
  60. Ulverscroft Vision Research Group, University College London, London, UK

    • Jugnoo S. Rahi
  61. Université de Bordeaux, Inserm, Bordeaux Population Health Research Center, team LEHA, UMR 1219, F-33000, Bordeaux, France

    • Cécile Delcourt
  62. Institut Pasteur de Lille, Lille, France

    • Céline Bellenguez
  63. Inserm, U1167, RID-AGE–Risk factors and molecular determinants of aging-related diseases, Lille, France

    • Céline Bellenguez
  64. Université de Lille, U1167–Excellence Laboratory LabEx DISTALZ, Lille, France

    • Céline Bellenguez
  65. Research Unit of Molecular Epidemiology, Institute of Epidemiology, Helmholtz Zentrum München–German Research Center for Environmental Health, Neuherberg, Germany

    • Angela Döring
    • , Janina S. Ried
    •  & Christian Gieger
  66. Department of Ophthalmology, Academic Medical Center, Amsterdam, The Netherlands

    • Arthur A. Bergen
  67. Netherlands Institute for Neurosciences (NIN-KNAW), Amsterdam, The Netherlands

    • Arthur A. Bergen
  68. Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany

    • Thomas Meitinger
  69. Institute of Human Genetics, Klinikum rechts der Isar, Technische Universität München, Munich, Germany

    • Thomas Meitinger
  70. Academic Medicine Research Institute, Singapore, Singapore

    • Tien Yin Wong
  71. Retino Center, Singapore National Eye Centre, Singapore, Singapore

    • Tien Yin Wong
  72. Department of Ophthalmology, Menzies Institute of Medical Research, University of Tasmania, Hobart, Tasmania, Australia

    • Alex W. Hewitt
    •  & David A. Mackey
  73. Centre for Ophthalmology and Visual Science, Lions Eye Institute, University of Western Australia, Perth, Western Australia, Australia

    • Seyhan Yazar
    • , Alex W. Hewitt
    •  & David A. Mackey
  74. Department of Genetics, Genomics and Informatics, University of Tennessee Health Sciences Center, Memphis, TN, USA

    • Claire L. Simpson
  75. Department of Ophthalmology, Central Hospital of Central Finland, Jyväskylä, Finland

    • Olavi Pärssinen
  76. Gerontology Research Center, Faculty of Sport and Health Sciences, University of Jyväskylä, Jyväskylä, Finland

    • Taina Rantanen
    •  & Olavi Pärssinen
  77. Myopia Research Group, Singapore Eye Research Institute, Singapore National Eye Centre, Singapore, Singapore

    • Seang-Mei Saw
  78. Department of Ophthalmology, Radboud University Medical Center, Nijmegen, The Netherlands

    • Caroline C. W. Klaver
  79. Singapore Eye Research Institute, Singapore National Eye Centre, Singapore, Singapore

    • Tin Aung
    •  & Amutha B. Veluchamy
  80. Department of Ophthalmology, National University Health Systems, National University of Singapore, Singapore, Singapore

    • Tin Aung
    • , Peng Chen
    •  & Chiea-Chuen Khor
  81. Duke-NUS Medical School, Singapore, Singapore, Singapore

    • Amutha B. Veluchamy
  82. Department of Ophthalmology and Visual Sciences, Chinese University of Hong Kong, Hong Kong Eye Hospital, Kowloon, Hong Kong

    • Li Jia Chen
    • , Vishal Jhanji
    • , Chi Pui Pang
    •  & Pancy O. Tam
  83. School of Ophthalmology and Optometry, Eye Hospital, Wenzhou Medical University, Wenzhou, China

    • Wei Chen
    •  & Xiangtian Zhou
  84. Department of Ophthalmology and Visual Sciences, John Moran Eye Center, University of Utah, Salt Lake City, UT, USA

    • Margaret M. Deangelis
    • , Chiea-Chuen Khor
    •  & Margaux Morrison
  85. State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China

    • Xiaohu Ding
    • , Xiaobo Guo
    •  & Mingguang He
  86. Translational Research Institute, University of Queensland Diamantina Institute, Brisbane, Queensland, Australia

    • David M. Evans
  87. MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK

    • David M. Evans
    • , Laura D. Howe
    • , John P. Kemp
    • , George McMahon
    • , George D. Smith
    • , Beate St Pourcain
    •  & Nicholas J. Timpson
  88. Department of Pediatric Ophthalmology, Duke Eye Center For Human Genetics, Durham, NC, USA

    • Sheng Feng
  89. Princess Alexandra Eye Pavilion, Edinburgh, UK

    • Brian Fleck
  90. University Hospital ‘San Giovanni di Dio’, Cagliari, Italy

    • Maurizio Fossarello
  91. Department of Statistical Science, School of Mathematics, Sun Yat-Sen University, Guangzhou, China

    • Xiaobo Guo
  92. School of Social and Community Medicine, University of Bristol, Bristol, UK

    • Laura D. Howe
  93. Department of Clinical Physiology, Tampere University Hospital and School of Medicine, University of Tampere, Tampere, Finland

    • Mika Kähönen
  94. Institute for Molecular Medicine Finland FIMM, HiLIFE Unit, University of Helsinki, Helsinki, Finland

    • Jaakko Kaprio
  95. Division of Human Genetics, Genome Institute of Singapore, Singapore, Singapore

    • Chiea-Chuen Khor
  96. MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London, UK

    • Eva Krapohl
    •  & Robert Plomin
  97. Université de Bordeaux, Bordeaux, France

    • Jean-François Korobelnik
  98. Institut National de la Santé Et de la Recherche Médicale (INSERM), Institut de Santé Publique d’Épidémiologie et de Développement (ISPED), Centre INSERM U897–Epidemiologie-Biostatistique, Bordeaux, France

    • Jean-François Korobelnik
  99. Department of Ophthalmology, Yokohama City University School of Medicine, Yokohama, Japan

    • Akira Meguro
    •  & Nobuhisa Mizuki
  100. Suraj Eye Institute, Nagpur, Maharashtra, India

    • Vinay Nangia
    •  & Songhomitra Panda-Jonas
  101. Institute of Neurogenomics, Helmholtz Zentrum München, German Research Centre for Environmental Health, Neuherberg, Germany

    • Konrad Oexle
  102. Institute of Genetic and Biomedic Research, National Research Council, Cagliari, Italy

    • Mario Pirastu
    •  & Simona Vaccargiu
  103. Max Planck Institute for Psycholinguistics, Nijmegen, The Netherlands

    • Beate St Pourcain
  104. MRC Epidemiology Unit, Institute of Metabolic Sciences, University of Cambridge, Cambridge, UK

    • Nick J. Wareham
    •  & Jing Hua Zhao
  105. Centre for Myopia Research, School of Optometry, Hong Kong Polytechnic University, Hong Kong, Hong Kong

    • Maurice K. H. Yap
  106. Department of Health Technology and Informatics, Hong Kong Polytechnic University, Hong Kong, Hong Kong

    • Shea Ping Yip
  107. Manchester Royal Eye Hospital, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK

    • Tariq M. Aslam
    •  & Paul N. Bishop
  108. School of Computer Science and Mathematics, Kingston University, Surrey, UK

    • Sarah A. Barman
  109. Section of Epidemiology and Biostatistics, Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, UK

    • Jenny H. Barrett
  110. Primary Care & Public Health Sciences, King’s College London, London, UK

    • Catey Bunce
  111. Faculty of Medicine University of Southampton, Southampton General Hospital, Southampton, UK

    • Roxana O. Carare
    • , Sarah Ennis
    •  & Jane Gibson
  112. School of Medicine, Dentistry and Biomedical Sciences, Queen’s University Belfast, Belfast, Northern Ireland, UK

    • Usha Chakravarthy
    •  & Tunde Peto
  113. Optometry and Visual Science, School of Health Science, City, University of London, London, UK

    • David Crabb
  114. Division of Health Sciences & Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK

    • Bal Dhillon
  115. School of Clinical Sciences, Faculty of Medicine and Dentistry, University of Bristol, Bristol, UK

    • Andrew D. Dick
  116. Department of Psychiatry, Oxford University, Warneford Hospital, Oxford, UK

    • John Gallacher
  117. Department of Eye and Vision Science, University of Liverpool, Liverpool, UK

    • Simon P. Harding
    •  & Yalin Zheng
  118. Centre for Experimental Medicine, Queen’s University Belfast, Belfast, Northern Ireland, UK

    • Ruth E. Hogg
  119. Department of Ophthalmology, University of Southampton NHS Foundation Trust, Southampton, UK

    • Andrew Lotery
    •  & Jay E. Self
  120. Edinburgh Imaging, University of Edinburgh, Edinburgh, UK

    • Tom J. MacGillivray
  121. Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, UK

    • Sarah L. Mackie
  122. Department of Ophthalmology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK

    • Keith R. Martin
  123. Centre for Public Health, Queen’s University Belfast, Belfast, Northern Ireland, UK

    • Michelle McGaughey
    • , Bernadette McGuinness
    • , Gareth J. McKay
    • , Euan N. Paterson
    •  & Jayne V. Woodside
  124. Department of Ophthalmology, Leeds Teaching Hospitals NHS Trust, Leeds, UK

    • Martin McKibbin
  125. Department of Ophthalmology, King’s College Hospital NHS Foundation Trust, London, UK

    • Eoin O’Sullivan
  126. St George’s, University of London, London, UK

    • Chris Owen
    •  & Alicja R. Rudnicka
  127. UCL Institute of Neurology, London, UK

    • Axel Petzold
  128. Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK

    • Jay E. Self
  129. Institute of Genetic Medicine, Newcastle University, Newcastle Upon Tyne, UK

    • David H. W. Steel
  130. Gloucestershire Retinal Research Group, Gloucestershire Hospitals NHS Foundation Trust, Cheltenham General Hospital, Cheltenham, UK

    • Irene M. Stratton
  131. Centre for Medical Informatics, Usher Institute for Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, UK

    • Cathie L. M. Sudlow
  132. School of Science and Engineering, University of Dundee, Dundee, UK

    • Emanuele Trucco
  133. Nottingham University Hospitals NHS Trust, Nottingham, UK

    • Stephen A. Vernon
  134. Norwich Medical School, University of East Anglia, Norwich, Norfolk, UK

    • Max Yates

Authors

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  95. Search for Jeremy A. Guggenheim in:

  96. Search for Joyce Y. Tung in:

  97. Search for Christopher J. Hammond in:

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Consortia

  1. The CREAM Consortium

  1. 23andMe Research Team

  1. UK Biobank Eye and Vision Consortium

Contributions

M.S.T., V.J.M.V., S.M., J.A.G., A.I.I., R.W., P.G.H., A.I.I. and E.M.v.L. performed the analyses. C.C.W.K., V.J.M.V., M.S.T., R.W., J.A.G. and S.M. drafted the manuscript, and C.J.H., P.G.H., A.P.K., C.M.v.D., D.S., E.M.v.L., J.E.B.-W., J.Y.T., N.A.F., Q.F., S.-M.S. and V.V. critically reviewed the manuscript. A.N., A.P.K., A.T., C.B., C. Gieger, C.L.S., C.-Y.C., G. Biino, G.C.-P., I.R., J.E.B.W., J.E.H., J. S. Ried, J.W., J.X., K.M.W., K.Y., P.M.C., S.M.H., M.S.T., N.A.F., N.E., P.C., P. Gharahkhani, P.K.J., Q.F., R. Höhn, R.L.S., R.P.I., R.W., T.H., T.-H.S.-A., T.Z., V.V., W.-Y.S., W.Z., X.L.S., Y.C.T., Y.S. and Y.Y.T. performed data analysis for the individual studies; A.D.P., A.G.U., A.T., A.W.H., B.E.K.K., C.C.W.K., C.D., C. Grazal, C.H., C.J.H., C.W., C.-Y.C., D.A.M., F.R., G. Bencic, H.M.-H., J.A.G., J.B.J., J.E.B.-W., J.E.C., J.F.W., J.H.L., J.R.V., J. S. Rahi, J. S. Ried, J.Y.T., K.Y., M.A.M.-S., N.G.M., N.P., O. Polašek, O. Pärssinen, O.T.R., P. Gupta, P.J.F., P.M., P.N.B., R.K., S.K.I., S.-M.S., T.L., T.M., W.Z., Y.C.T. and Y.X.W. contributed to data assembly. A.A.B.B., A.W., C. Grazal, D.S., K.N.W., S.W.T. and T.L.Y. performed expression experiments, and M.S.T., A.A.B.B., P.J.v.d.S. and R. Hask performed in silico pathway analyses. C.C.W.K. and C.J.H. conceived and designed the outline of the current report, and supervised conduction of experiments and analyses jointly with A.M., A.H., A.W.H., C.D., C.H., C.J.H., C.M.v.D., C.W., C.-Y.C., D.A.M., D.S., E.-S.T., F.M., G. Biino, I.R., J.A.G., J.B.J., J.E.B.-W., J.E.C., J.F.W., J.H.L., J.R.V., J.Y.T., N.A., N.A.F., N.P., O. Pärssinen, O.T.R., P.J.F., P.N.B., S.K.I., S.-M.S., T.L., T.Y.W., T.L.Y., V.V., Y.X.W. and Y.Y.T. M.P.C. analyzed the data and performed statistical analyses. The 23andMe research team, CREAM and the UK Biobank Eye and Vision Consortium contributed reagents/materials/analysis tools and performed statistical analyses.

Competing interests

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.

Corresponding author

Correspondence to Caroline C. W. Klaver.

Supplementary information

  1. Supplementary Text and Figures

    Supplementary Figures 1–12, Supplementary Note and Supplementary Tables 1, 5–9, 12 and 17

  2. Reporting Summary

  3. Supplementary Table 2

    Stage 1 - 3 Meta-Analyses and Conditional Analysis

  4. Supplementary Table 3

    Stage 3 Index Variants of FE and RE analyses

  5. Supplementary Table 4

    HWE p-value per cohort TopSNPs Stage 3

  6. Supplementary Table 10

    DEPICT analysis - gene-set enrichment

  7. Supplementary Table 11

    Ranking of associated genes according to biological plausibility

  8. Supplementary Table 13

    Genes with Human Ocular Phenotypes

  9. Supplementary Table 14

    Genes with Mice Ocular Phenotypes

  10. Supplementary Table 15

    Expression of Candidate Genes in Ocular Tissues

  11. Supplementary Table 16

    Genetic variants harboring known drug targets

  12. Supplementary Data 1

    Locus Zoom Plots

  13. Supplementary Data 2

    Forest Plots Stage 3 and Conditional Loci

  14. Supplementary Data 3

    Summary Statistics Stage 3 Meta-analysis

The CREAM Consortium23andMe Research TeamUK Biobank Eye and Vision ConsortiumSupplementary information

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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DOI

https://doi.org/10.1038/s41588-018-0127-7

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