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

Journal name:
Nature Genetics
Volume:
45,
Pages:
314–318
Year published:
DOI:
doi:10.1038/ng.2554
Received
Accepted
Published online
Corrected online

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.

At a glance

Figures

  1. Manhattan plot of the GWAS meta-analysis for refractive error in the combined analysis (n = 45,758).
    Figure 1: Manhattan plot of the GWAS meta-analysis for refractive error in the combined analysis (n = 45,758).

    The plot shows −log10-transformed P values for all SNPs. The upper horizontal line represents the genome-wide significance threshold of P < 5.0 × 10−8; the lower line indicates P value of 1 × 10−5. Previously reported genes are shown in gray. The RBFOX1 gene is also known as A2BP1.

  2. Genetic risk score for myopia.
    Figure 2: Genetic risk score for myopia.

    Distribution of subjects from Rotterdam Study 1–3 (n = 9,307) with myopia (SE ≤ −3 diopters (D)), emmetropia (SE ≥ −1.5 D and ≤ 1.5 D) and hyperopia (SE ≥ 3 D) as a function of the genetic risk score. This score is based on the regression coefficients and allele dosages of the associated SNPs for all 26 loci identified in the meta-analysis. Mean OR of myopia was calculated per risk category, using the middle risk score category (risk score of 2.50–2.75) as a reference.

Accession codes

Primary accessions

Referenced accessions

Gene Expression Omnibus

Change history

Corrected online 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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Author information

  1. These authors contributed equally to this work.

    • Virginie J M Verhoeven,
    • Pirro G Hysi,
    • Robert Wojciechowski,
    • Qiao Fan,
    • Jeremy A Guggenheim &
    • René Höhn
  2. These authors jointly directed this work.

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

Affiliations

  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. A full list of members appears in the Supplementary Note.

    • $affiliationAuthor
  36. Institute of Epidemiology I, Helmholtz Zentrum München–German Research Center for Environmental Health, Neuherberg, Germany.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

    • Sudha K Iyengar
  54. 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
  55. Centre for Population Health Sciences, University of Edinburgh, Edinburgh, UK.

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

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

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

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

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

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

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

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

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

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

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

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

    • Dwight Stambolian

Consortia

  1. Consortium for Refractive Error and Myopia (CREAM)

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

  3. Wellcome Trust Case Control Consortium 2 (WTCCC2)

  4. The Fuchs' Genetics Multi-Center Study Group

Contributions

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.

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The authors declare no competing financial interests.

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    Supplementary Tables 1–4, Supplementary Figures 1–5 and Supplementary Note

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