Abstract

Refractive errors are the most common ocular disorders worldwide and may lead to blindness. Although this trait is highly heritable, identification of susceptibility genes has been challenging. We conducted a genome-wide association study for refractive error in 5,328 individuals from a Dutch population-based study with replication in four independent cohorts (combined 10,280 individuals in the replication stage). We identified a significant association at chromosome 15q14 (rs634990, P = 2.21 × 10−14). The odds ratio of myopia compared to hyperopia for the minor allele (minor allele frequency = 0.47) was 1.41 (95% CI 1.16–1.70) for individuals heterozygous for the allele and 1.83 (95% CI 1.42–2.36) for individuals homozygous for the allele. The associated locus is near two genes that are expressed in the retina, GJD2 and ACTC1, and appears to harbor regulatory elements which may influence transcription of these genes. Our data suggest that common variants at 15q14 influence susceptibility for refractive errors in the general population.

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Acknowledgements

Major funding of the work performed in The Netherlands came from the Netherlands Organisation of Scientific Research (NWO); Erasmus Medical Center and Erasmus University, Rotterdam, The Netherlands; Netherlands Organization for Health Research and Development (ZonMw); UitZicht; the Research Institute for Diseases in the Elderly; the Ministry of Education, Culture and Science; the Ministry for Health, Welfare and Sports; the European Commission (DG XII); the Municipality of Rotterdam; the Netherlands Genomics Initiative (NGI)/NWO; Center for Medical Systems Biology of NGI; Lijf en Leven; M.D. Fonds; H. Stichting; Oogfonds Nederland; Stichting Nederlands Oogheelkundig Onderzoek; Swart van Essen; Bevordering van Volkskracht; Blindenhulp; Landelijke Stichting voor Blinden en Slechtzienden; Rotterdamse Vereniging voor Blindenbelangen; OOG; Algemene Nederlandse Vereniging ter Voorkoming van Blindheid; the Rotterdam Eye Hospital Research Foundation; Laméris Ootech; Topcon Europe; and Heidelberg Engineering. We thank A. Hooghart, C. Brussee, R. Bernaerts-Biskop, P. van Hilten, P. Arp, M. Jhamai, M. Moorhouse, J. Vergeer, M. Verkerk, S. Bervoets and P. van der Spek for help in execution of the study.

TwinsUK acknowledges the Wellcome Trust, the European Union MyEuropia Marie Curie Research Training Network, Guide Dogs for the Blind Association, the European Community's Seventh Framework Programme (FP7/2007-2013)/grant agreement HEALTH-F2-2008-201865-GEFOS and (FP7/2007-2013), European Network of Genetic and Genomic Epidemiology (ENGAGE) project grant agreement HEALTH-F4-2007-201413 and the FP-5 GenomEUtwin Project (QLG2-CT-2002-01254), Biotechnology and Biological Sciences Research Council (G20234), Department of Health via US National Institutes of Health, (National Eye Institute grant RO1EY018246), and the Center for Inherited Disease Research. TwinsUK thanks G. Surdulescu, L. Peltonen, P. Deloukas, M. Lathrop, D. Goldstein, A. Palotie and C. Day for help in execution of the study and analyses.

Author information

Author notes

    • Abbas M Solouki
    •  & Virginie J M Verhoeven

    These authors contributed equally to this work.

Affiliations

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

    • Abbas M Solouki
    • , Virginie J M Verhoeven
    • , M Kamran Ikram
    • , Dominiek D G Despriet
    • , Leonieke M van Koolwijk
    • , Lintje Ho
    • , Wishal D Ramdas
    • , Monika Czudowska
    • , Robert W A M Kuijpers
    • , Gabriel van Rij
    • , Johannes R Vingerling
    •  & Caroline C W Klaver
  2. Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.

    • Abbas M Solouki
    • , Virginie J M Verhoeven
    • , Cornelia M van Duijn
    • , M Kamran Ikram
    • , Dominiek D G Despriet
    • , Lintje Ho
    • , Wishal D Ramdas
    • , Monika Czudowska
    • , Najaf Amin
    • , Maksim Struchalin
    • , Yurii S Aulchenko
    • , Aaron Isaacs
    • , Andy A L J van Oosterhout
    • , Fernando Rivadeneira
    • , André G Uitterlinden
    • , Albert Hofman
    • , Paulus T V M de Jong
    • , Johannes R Vingerling
    •  & Caroline C W Klaver
  3. Department of Bioinformatics, Erasmus Medical Center, Rotterdam, The Netherlands.

    • Annemieke J M H Verkerk
    •  & Sigrid M A Swagemakers
  4. Department of Neurology, Erasmus Medical Center, Rotterdam, The Netherlands.

    • M Kamran Ikram
  5. Department of Twin Research and Genetic Epidemiology, King's College London School of Medicine, London, UK.

    • Pirro G Hysi
    • , Timothy D Spector
    •  & Christopher J Hammond
  6. The Rotterdam Eye Hospital, Rotterdam, The Netherlands.

    • Leonieke M van Koolwijk
  7. Bartiméus, Institute for the Visually Impaired, Zeist, The Netherlands.

    • Frans C C Riemslag
  8. Center for Human Genetics, Duke University, Durham, North Carolina, USA.

    • Terri L Young
  9. Lions Eye Institute, University of Western Australia, Centre for Ophthalmology and Visual Science, Perth, Australia.

    • David A Mackey
  10. 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
    •  & Paulus T V M de Jong
  11. Department of Ophthalmology, Amphia Hospital, Breda, The Netherlands.

    • Jacqueline J M Willemse-Assink
  12. Department of Ophthalmology, Fransiscus Hospital, Roosendaal, The Netherlands.

    • Rogier Kramer
  13. Department of Genetics, Erasmus Medical Center, Rotterdam, The Netherlands.

    • Sigrid M A Swagemakers
  14. The Cancer Genomics Center, Rotterdam, The Netherlands.

    • Sigrid M A Swagemakers
  15. Department of Clinical Genetics, Academic Medical Center, Amsterdam, The Netherlands.

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

    • Arthur A B Bergen
  17. Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands.

    • Andy A L J van Oosterhout
    •  & Ben A Oostra
  18. Department of Internal Medicine and Clinical Chemistry, Erasmus Medical Center, Rotterdam, The Netherlands.

    • Fernando Rivadeneira
    •  & André G Uitterlinden

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Contributions

A.M.S., V.J.M.V. and C.C.W.K. performed analyses and drafted the manuscript. C.M.v.D., B.A.O., F.R., A.G.U., A.H., P.T.V.M.d.J., J.R.V. and C.C.W.K. designed the study and obtained funding. D.D.G.D., L.M.v.K., L.H., W.D.R., M.C., R.K., J.J.M.W.-A., T.G.M.F.G., F.C.C.R. and S.M.A.S. helped in data collection. A.J.M.H.V., M.K.I., N.A., M.S., Y.S.A., A.A.B.B., A.A.L.J.v.O. and A.I. participated in the genetic analyses. P.G.H., T.L.Y., D.A.M., T.D.S. and C.J.H. were responsible for data from the TwinsUK study. M.K.I., R.W.A.M.K., G.v.R., P.G.H., C.J.H., C.M.v.D., A.J.M.H.V., B.A.O., J.R.V. and A.A.B.B. critically reviewed the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Caroline C W Klaver.

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DOI

https://doi.org/10.1038/ng.663

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