Letter | Published:

Genome-wide meta-analyses of multiancestry cohorts identify multiple new susceptibility loci for refractive error and myopia

Nature Genetics volume 45, pages 314318 (2013) | Download Citation

  • A Corrigendum to this article was published on 29 May 2013

This article has been updated


Refractive error is the most common eye disorder worldwide and is a prominent cause of blindness. Myopia affects over 30% of Western populations and up to 80% of Asians. The CREAM consortium conducted genome-wide meta-analyses, including 37,382 individuals from 27 studies of European ancestry and 8,376 from 5 Asian cohorts. We identified 16 new loci for refractive error in individuals of European ancestry, of which 8 were shared with Asians. Combined analysis identified 8 additional associated loci. The new loci include candidate genes with functions in neurotransmission (GRIA4), ion transport (KCNQ5), retinoic acid metabolism (RDH5), extracellular matrix remodeling (LAMA2 and BMP2) and eye development (SIX6 and PRSS56). We also confirmed previously reported associations with GJD2 and RASGRF1. Risk score analysis using associated SNPs showed a tenfold increased risk of myopia for individuals carrying the highest genetic load. Our results, based on a large meta-analysis across independent multiancestry studies, considerably advance understanding of the mechanisms involved in refractive error and myopia.

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Change history

  • 09 May 2013

    In the version of this article initially published, the affiliations of Daniel W.H. Ho were incorrect, and the spelling of Sarayut Janmahasatian in the author list was incorrect. The errors have been corrected in the HTML and PDF versions of this article.


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We gratefully thank the invaluable contributions of all study participants, their relatives and staff at the recruitment centers. Complete funding information and acknowledgments by study can be found in the Supplementary Note.

Author information

Author notes

    • Virginie J M Verhoeven
    • , Pirro G Hysi
    • , Robert Wojciechowski
    • , Qiao Fan
    • , Jeremy A Guggenheim
    •  & René Höhn

    These authors contributed equally to this work.

    • Seang-Mei Saw
    • , Joan E Bailey-Wilson
    • , Dwight Stambolian
    • , Caroline C Klaver
    •  & Christopher J Hammond

    These authors jointly directed this work.


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

    • Virginie J M Verhoeven
    • , Gabriëlle H S Buitendijk
    • , Johannes R Vingerling
    •  & Caroline C Klaver
  2. Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.

    • Virginie J M Verhoeven
    • , Gabriëlle H S Buitendijk
    • , Lennart C Karssen
    • , André G Uitterlinden
    • , Fernando Rivadeneira
    • , Johannes R Vingerling
    • , Albert Hofman
    • , Najaf Amin
    • , Cornelia M van Duijn
    •  & Caroline C Klaver
  3. Department of Twin Research and Genetic Epidemiology, King's College London School of Medicine, London, UK.

    • Pirro G Hysi
    • , Abhishek Nag
    • , Ekaterina Yonova-Doing
    • , Tim D Spector
    •  & Christopher J Hammond
  4. Inherited Disease Research Branch, National Human Genome Research Institute, US National Institutes of Health, Baltimore, Maryland, USA.

    • Robert Wojciechowski
    • , Claire L Simpson
    •  & Joan E Bailey-Wilson
  5. Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.

    • Robert Wojciechowski
  6. Saw Swee Hock School of Public Health, National University Health Systems, National University of Singapore, Singapore.

    • Qiao Fan
    • , Ching-Yu Cheng
    • , Xin Zhou
    • , M Kamran Ikram
    • , Chiea-Chuen Khor
    • , E-Shyong Tai
    • , Peng Chen
    • , Ruoying Li
    • , Rick T Ong
    • , Yik-Ying Teo
    • , Tien-Yin Wong
    •  & Seang-Mei Saw
  7. Centre for Myopia Research, School of Optometry, The Hong Kong Polytechnic University, Hong Kong.

    • Jeremy A Guggenheim
    •  & Daniel W H Ho
  8. Department of Ophthalmology, University Medical Center Mainz, Mainz, Germany.

    • René Höhn
    • , Alireza Mirshahi
    •  & Norbert Pfeiffer
  9. Department of Statistical Genetics, Queensland Institute of Medical Research, Herston, Brisbane, Queensland, Australia.

    • Stuart MacGregor
    •  & Aniket Mishra
  10. Centre for Eye Research Australia (CERA), University of Melbourne, Royal Victorian Eye and Ear Hospital, Melbourne, Victoria, Australia.

    • Alex W Hewitt
    • , Jie Jin Wang
    • , Maria Schache
    • , Paul N Baird
    •  & David A Mackey
  11. Centre for Ophthalmology and Visual Science, Lions Eye Institute, University of Western Australia, Perth, Western Australia, Australia.

    • Alex W Hewitt
    •  & David A Mackey
  12. Department of Ophthalmology, National University Health Systems, National University of Singapore, Singapore.

    • Ching-Yu Cheng
    • , M Kamran Ikram
    • , Chiea-Chuen Khor
    • , Tin Aung
    • , Veluchamy A Barathi
    • , Jiemin Liao
    • , Tien-Yin Wong
    •  & Seang-Mei Saw
  13. Singapore Eye Research Institute, Singapore National Eye Centre, Singapore.

    • Ching-Yu Cheng
    • , M Kamran Ikram
    • , Tin Aung
    • , Eranga Vithana
    • , Wan-Ting Tay
    • , Veluchamy A Barathi
    • , Yingfeng Zheng
    • , Tien-Yin Wong
    •  & Seang-Mei Saw
  14. Medical Research Council Centre for Causal Analyses in Translational Epidemiology, School of Social and Community Medicine, University of Bristol, Bristol, UK.

    • George McMahon
    • , John P Kemp
    • , David M Evans
    •  & Nicholas J Timpson
  15. School of Social and Community Medicine, University of Bristol, Bristol, UK.

    • Beate St Pourcain
    •  & Cathy Williams
  16. Department of Clinical Chemistry, Fimlab Laboratories and School of Medicine, University of Tampere, Tampere, Finland.

    • Kari-Matti Mäkelä
    •  & Terho Lehtimäki
  17. Department of Clinical Physiology, Tampere University Hospital and School of Medicine, University of Tampere, Tampere, Finland.

    • Mika Kähönen
  18. Program in Genetics and Genome Biology, Hospital for Sick Children and University of Toronto, Toronto, Ontario, Canada.

    • Andrew D Paterson
    • , S Mohsen Hosseini
    •  & Hoi Suen Wong
  19. Beijing Institute of Ophthalmology, Beijing Tongren Hospital, Capital Medical University, Beijing, China.

    • Liang Xu
  20. Department of Ophthalmology, Medical Faculty Mannheim, Ruprecht-Karls-University Heidelberg, Mannheim, Germany.

    • Jost B Jonas
  21. Department of Health Sciences, University of Jyväskylä, Jyväskylä, Finland.

    • Olavi Pärssinen
  22. Gerontology Research Center, University of Jyväskylä, Jyväskylä, Finland.

    • Olavi Pärssinen
  23. Department of Ophthalmology, Central Hospital of Central Finland, Jyväskylä, Finland.

    • Olavi Pärssinen
  24. Department of Public Health, Hjelt Institute, University of Helsinki, Helsinki, Finland.

    • Juho Wedenoja
  25. Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Hong Kong.

    • Shea Ping Yip
    •  & Daniel W H Ho
  26. Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Hong Kong Eye Hospital, Kowloon, Hong Kong.

    • Chi Pui Pang
  27. Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong.

    • Li Jia Chen
  28. Department of Ophthalmology, Flinders University, Adelaide, South Australia, Australia.

    • Kathryn P Burdon
    •  & Jamie E Craig
  29. Department of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA.

    • Barbara E K Klein
    •  & Ronald Klein
  30. Estonian Genome Center, University of Tartu, Tartu, Estonia.

    • Toomas Haller
    •  & Andres Metspalu
  31. Department of Pediatrics, National University of Singapore, Singapore.

    • Chiea-Chuen Khor
  32. Division of Human Genetics, Genome Institute of Singapore, Singapore.

    • Chiea-Chuen Khor
  33. Department of Medicine, National University of Singapore, Singapore.

    • E-Shyong Tai
  34. Duke–National University of Singapore Graduate Medical School, Singapore.

    • E-Shyong Tai
    • , Veluchamy A Barathi
    •  & Seang-Mei Saw
  35. Institute of Epidemiology I, Helmholtz Zentrum München–German Research Center for Environmental Health, Neuherberg, Germany.

    • Angela Döring
  36. Institute of Epidemiology II, Helmholtz Zentrum München–German Research Center for Environmental Health, Neuherberg, Germany.

    • Angela Döring
    •  & André G Uitterlinden
  37. Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.

    • Annemieke J M H Verkerk
    •  & Fernando Rivadeneira
  38. Institute of Human Genetics, Technical University Munich, Munich, Germany.

    • Thomas Meitinger
    •  & Konrad Oexle
  39. Research Centre of Applied and Preventive Medicine, University of Turku, Turku, Finland.

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

    • Olli Raitakari
  41. Department of Pediatric Ophthalmology, Duke Eye Center For Human Genetics, Durham, North Carolina, USA.

    • Felicia Hawthorne
    •  & Terri L Young
  42. Institute of Population Genetics, National Research Council, Sassari, Italy.

    • Mario Pirastu
    •  & Federico Murgia
  43. School of Women's and Infants' Health, University of Western Australia, Perth, Western Australia, Australia.

    • Wei Ang
    •  & Craig E Pennell
  44. Department of Molecular Epidemiology, Queensland Institute of Medical Research, Herston, Brisbane, Queensland, Australia.

    • Grant W Montgomery
    •  & Jugnoo S Rahi
  45. Medical Research Council Centre of Epidemiology for Child Health, Institute of Child Health, University College London, London, UK.

    • Phillippa M Cumberland
  46. Ulverscroft Vision Research Group, University College London, London, UK.

    • Phillippa M Cumberland
    •  & Jugnoo S Rahi
  47. Imperial College Cerebrovascular Research Unit (ICCRU), Division of Brain Sciences, Department of Medicine, Imperial College London, London, UK.

    • Ioana Cotlarciuc
  48. Department of Ophthalmology, Centre for Vision Research, Westmead Millennium Institute, University of Sydney, Sydney, New South Wales, Australia.

    • Paul Mitchell
    •  & Jie Jin Wang
  49. Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, Ohio, USA.

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

    • Jonathan H Lass
    •  & Sudha K Iyengar
  51. National Eye Institute, US National Institutes of Health, Bethesda, Maryland, USA.

    • Emily Chew
  52. Department of Genetics, Case Western Reserve University, Cleveland, Ohio, USA.

    • Sudha K Iyengar
  53. Department of Clinical and Molecular Ophthalmogenetics, Netherlands Institute of Neurosciences (NIN; an Institute of the Royal Netherlands Academy of Arts and Sciences (KNAW), Amsterdam, The Netherlands.

    • Theo G M F Gorgels
    •  & Arthur A B Bergen
  54. Centre for Population Health Sciences, University of Edinburgh, Edinburgh, UK.

    • Igor Rudan
    •  & James F Wilson
  55. Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.

    • Caroline Hayward
    • , Alan F Wright
    •  & Veronique Vitart
  56. Faculty of Medicine, University of Split, Split, Croatia.

    • Ozren Polasek
  57. Department of Ophthalmology, Sisters of Mercy University Hospital, Zagreb, Croatia.

    • Zoran Vatavuk
  58. Princess Alexandra Eye Pavilion, Edinburgh, UK.

    • Brian Fleck
  59. Clinic for General and Interventional Cardiology, University Heart Center Hamburg, Hamburg, Germany.

    • Tanja Zeller
    •  & Christian Müller
  60. Netherlands Consortium for Healthy Ageing, Netherlands Genomics Initiative, The Hague, The Netherlands.

    • André G Uitterlinden
    • , Fernando Rivadeneira
    •  & Albert Hofman
  61. Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands.

    • Ben A Oostra
  62. Department of Clinical Genetics, Academic Medical Center, Amsterdam, The Netherlands.

    • Arthur A B Bergen
  63. Department of Ophthalmology, Academic Medical Center, Amsterdam, The Netherlands.

    • Arthur A B Bergen
  64. Department of Statistics and Applied Probability, National University of Singapore, Singapore.

    • Yik-Ying Teo
  65. Institute of Ophthalmology, Moorfields Eye Hospital, London, UK.

    • Jugnoo S Rahi
  66. Department of Ophthalmology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

    • Dwight Stambolian


  1. Consortium for Refractive Error and Myopia (CREAM)

    A full list of members appears in the Supplementary Note.

  2. The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Research Group

    A full list of members appears in the Supplementary Note.

  3. Wellcome Trust Case Control Consortium 2 (WTCCC2)

    A full list of members appears in the Supplementary Note.

  4. The Fuchs' Genetics Multi-Center Study Group

    A full list of members appears in the Supplementary Note.


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V.J.M.V., P.G.H., R.W., C.J.H., C.C.W.K., A.W.H., D.A.M., T.L.Y. and C.M.v.D. performed analyses and drafted the manuscript. C.C.W.K., D.S., C.J.H., J.E.B.-W., S.-M.S., C.M.v.D., A.H., D.A.M., S.M., A.D.P., V.V., C.W., P.N.B., T.-Y.W., J.S.R., T.L.Y., K.O., O. Pärssinen, S.P.Y., J.A.G., A. Metspalu, M.P., S.K.I. and N.P. jointly conceived the project and supervised the work. J.E.B.W., S.-M.S., D.A.M., T.L.Y., C.J.H., C.C.W.K., D.S., J.E.B.-W., C.M.v.D., R.W., P.G.H., V.J.M.V., K.O., Y.-Y.T., T.-Y.W., P.N.B., V.V., N.A., B.A.O., A.H., J.R.V., F.R., A.G.U., N.P., C.M., A. Mirshahi, T.Z., B.F., J.F.W., Z.V., O. Polasek, A.F.W., C.H., I.R., S.K.I., E.C., J.H.L., R.P.I., S.J., M.S., J.J.W., P.M., I.C., J.S.R., P.M.C., C.E.P., G.W.M., A. Mishra, W.A., F.M., M.P., L.C.K., T.D.S., E.Y.-D., A.N., O.R., C.-C.K., T.M., A.D., R.T.O., Y.Z., J.L., R.L., P.C., V.A.B., W.-T.T., E.V., T.A., E.-S.T., A. Metspalu, T.H., R.K., B.E.K.K., J.E.C., K.P.B., L.J.C., C.P.P., D.W.H.H., S.P.Y., J.W., O. Pärssinen, J.B.J., L.X., H.S.W., S.M.H., A.D.P., M.K., T.L., K.-M.M., C.L.S., C.W., N.J.T., D.M.E., B.S.P., J.P.K., G.M., G.H.S.B., M.K.I., X.Z., C.-Y.C., A.W.H., S.M., R.H., J.A.G. and Q.F. were responsible for study-specific data. G.H.S.B., V.J.M.V., Q.F. and J.A.G. were involved in the genetic risk score analysis. T.L.Y., A.A.B.B., T.G.M.F.G. and F.H. performed the data expression experiments. A.A.B.B., T.G.M.F.G., A.M. and S.M. were involved in pathway analyses. J.E.B.-W., S.-M.S., D.A.M., T.L.Y., K.O., T.-Y.W., P.N.B., T.G.M.F.G., S.K.I., E.C., J.J.W., A.J.M.H.V., C.-C.K., B.E.K.K., S.P.Y., C.W., N.J.T., G.H.S.B., M.K.I., A.W.H. and J.A.G. critically reviewed the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Caroline C Klaver.

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