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A genome-wide association study for myopia and refractive error identifies a susceptibility locus at 15q25

Abstract

Myopia and hyperopia are at opposite ends of the continuum of refraction, the measure of the eye′s ability to focus light, which is an important cause of visual impairment (when aberrant) and is a highly heritable trait. We conducted a genome-wide association study for refractive error in 4,270 individuals from the TwinsUK cohort. We identified SNPs on 15q25 associated with refractive error (rs8027411, P = 7.91 × 10−8). We replicated this association in six adult cohorts of European ancestry with a combined 13,414 individuals (combined P = 2.07 × 10−9). This locus overlaps the transcription initiation site of RASGRF1, which is highly expressed in neurons and retina and has previously been implicated in retinal function and memory consolidation. Rasgrf1−/− mice show a heavier average crystalline lens (P = 0.001). The identification of a susceptibility locus for refractive error on 15q25 will be important in characterizing the molecular mechanism responsible for the most common cause of visual impairment.

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Figure 1: Association scatter plot for SNPs in the RASGRF1 promoter region in the TwinsUK discovery cohort.
Figure 2: Association of rs8027411 with clinical myopia in the TwinsUK cohort.
Figure 3: Plot of the effect on refractive error observed for rs8027411 in the seven population panels participating in the study.

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References

  1. Vitale, S., Ellwein, L., Cotch, M.F., Ferris, F.L. III & Sperduto, R. Prevalence of refractive error in the United States, 1999–2004. Arch. Ophthalmol. 126, 1111–1119 (2008).

    Article  Google Scholar 

  2. Morgan, I. & Rose, K. How genetic is school myopia? Prog. Retin. Eye Res. 24, 1–38 (2005).

    Article  Google Scholar 

  3. Wu, H.M. et al. Does education explain ethnic differences in myopia prevalence? A population-based study of young adult males in Singapore. Optom. Vis. Sci. 78, 234–239 (2001).

    Article  CAS  Google Scholar 

  4. Rein, D.B. et al. The economic burden of major adult visual disorders in the United States. Arch. Ophthalmol. 124, 1754–1760 (2006).

    Article  Google Scholar 

  5. Bamashmus, M.A., Matlhaga, B. & Dutton, G.N. Causes of blindness and visual impairment in the West of Scotland. Eye 18, 257–261 (2004).

    Article  CAS  Google Scholar 

  6. Evans, J.R., Fletcher, A.E. & Wormald, R.P. Causes of visual impairment in people aged 75 years and older in Britain: an add-on study to the MRC Trial of Assessment and Management of Older People in the Community. Br. J. Ophthalmol. 88, 365–370 (2004).

    Article  CAS  Google Scholar 

  7. Resnikoff, S., Pascolini, D., Mariotti, S.P. & Pokharel, G.P. Global magnitude of visual impairment caused by uncorrected refractive errors in 2004. Bull. World Health Organ. 86, 63–70 (2008).

    Article  Google Scholar 

  8. Buch, H. et al. Prevalence and causes of visual impairment and blindness among 9980 Scandinavian adults: the Copenhagen City Eye Study. Ophthalmology 111, 53–61 (2004).

    Article  Google Scholar 

  9. Saw, S.M., Katz, J., Schein, O.D., Chew, S.J. & Chan, T.K. Epidemiology of myopia. Epidemiol. Rev. 18, 175–187 (1996).

    Article  CAS  Google Scholar 

  10. Rose, K.A. et al. Outdoor activity reduces the prevalence of myopia in children. Ophthalmology 115, 1279–1285 (2008).

    Article  Google Scholar 

  11. Lopes, M.C., Andrew, T., Carbonaro, F., Spector, T.D. & Hammond, C.J. Estimating heritability and shared environmental effects for refractive error in twin and family studies. Invest. Ophthalmol. Vis. Sci. 50, 126–131 (2009).

    Article  Google Scholar 

  12. Vitale, S., Sperduto, R.D. & Ferris, F.L. III. Increased prevalence of myopia in the United States between 1971–1972 and 1999–2004. Arch. Ophthalmol. 127, 1632–1639 (2009).

    Article  Google Scholar 

  13. Zippel, R. et al. Ras-GRF, the activator of Ras, is expressed preferentially in mature neurons of the central nervous system. Brain Res. Mol. Brain Res. 48, 140–144 (1997).

    Article  CAS  Google Scholar 

  14. Raaijmakers, J.H. & Bos, J.L. Specificity in Ras and Rap signaling. J. Biol. Chem. 284, 10995–10999 (2009).

    Article  CAS  Google Scholar 

  15. de la Puente, A. et al. Structural characterization of Rasgrf1 and a novel linked imprinted locus. Gene 291, 287–297 (2002).

    Article  CAS  Google Scholar 

  16. Yoon, B.J. et al. Regulation of DNA methylation of Rasgrf1. Nat. Genet. 30, 92–96 (2002).

    Article  CAS  Google Scholar 

  17. Mattingly, R.R. & Macara, I.G. Phosphorylation-dependent activation of the Ras-GRF/CDC25Mm exchange factor by muscarinic receptors and G-protein beta gamma subunits. Nature 382, 268–272 (1996).

    Article  CAS  Google Scholar 

  18. Tonini, R. et al. Expression of Ras-GRF in the SK-N-BE neuroblastoma accelerates retinoic-acid-induced neuronal differentiation and increases the functional expression of the IRK1 potassium channel. Eur. J. Neurosci. 11, 959–966 (1999).

    Article  CAS  Google Scholar 

  19. Tigges, M. et al. Effects of muscarinic cholinergic receptor antagonists on postnatal eye growth of rhesus monkeys. Optom. Vis. Sci. 76, 397–407 (1999).

    Article  CAS  Google Scholar 

  20. Tong, L. et al. Atropine for the treatment of childhood myopia: effect on myopia progression after cessation of atropine. Ophthalmology 116, 572–579 (2009).

    Article  Google Scholar 

  21. Mertz, J.R. & Wallman, J. Choroidal retinoic acid synthesis: a possible mediator between refractive error and compensatory eye growth. Exp. Eye Res. 70, 519–527 (2000).

    Article  CAS  Google Scholar 

  22. Brambilla, R. et al. A role for the Ras signalling pathway in synaptic transmission and long-term memory. Nature 390, 281–286 (1997).

    Article  CAS  Google Scholar 

  23. Fernández-Medarde, A. et al. RasGRF1 disruption causes retinal photoreception defects and associated transcriptomic alterations. J. Neurochem. 110, 641–652 (2009).

    Article  Google Scholar 

  24. Schmucker, C. & Schaeffel, F. In vivo biometry in the mouse eye with low coherence interferometry. Vision Res. 44, 2445–2456 (2004).

    Article  Google Scholar 

  25. Zhou, X. et al. The development of the refractive status and ocular growth in C57BL/6 mice. Invest. Ophthalmol. Vis. Sci. 49, 5208–5214 (2008).

    Article  Google Scholar 

  26. Solouki, A. et al. A genome-wide association study for myopia and refractive error identifies a susceptibility locus at 15q14. Nat. Genet. advance online publication, doi:10.1038/ng.663 (12 September 2010).

  27. Deans, M.R., Volgyi, B., Goodenough, D.A., Bloomfield, S.A. & Paul, D.L. Connexin36 is essential for transmission of rod-mediated visual signals in the mammalian retina. Neuron 36, 703–712 (2002).

    Article  CAS  Google Scholar 

  28. Wallman, J. & Winawer, J. Homeostasis of eye growth and the question of myopia. Neuron 43, 447–468 (2004).

    Article  CAS  Google Scholar 

  29. Font de Mora, J. et al. Ras-GRF1 signaling is required for normal beta-cell development and glucose homeostasis. EMBO J. 22, 3039–3049 (2003).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The King's College London authors acknowledge funding from the Wellcome Trust, the European Union MyEuropia Marie Curie Research Training Network, Guide Dogs for the Blind Association, the European Community's FP7 (HEALTH-F2-2008-201865-GEFOS), European Network of Genetic and Genomic Epidemiology (ENGAGE) (HEALTH-F4-2007-201413), the FP-5 GenomEUtwin Project (QLG2-CT-2002-01254), US National Institutes of Health (NIH)/National Eye Institute (NEI) grant 1RO1EY018246 and genotyping by the NIH Center for Inherited Disease Research. The study also received support from the National Institute for Health Research (NIHR) comprehensive Biomedical Research Centre award to Guy's and St. Thomas' National Health Service Foundation Trust partnering with King's College London. We are grateful to the volunteer twins, C. Smoliner and M. Liew, and to R. Metlapally and Felicia Hawthorne in T.L.Y.'s laboratory for RASGRF1 expression studies.

The Rotterdam Study acknowledges Netherlands Organisation of Scientific Research (NWO); the Erasmus Medical Center; Netherlands Organization for the Health Research and Development (ZonMw); UitZicht; Research Institute for Diseases in the Elderly (RIDE); the European Commission Directorate-General XII; the Municipality of Rotterdam; Netherlands Genomics Initiative (NGI); Lijf en Leven; MD Fonds; Henkes; Oogfonds; Stichting Wetenschappelijk Onderzoek Het Oogziekenhuis (SWOO); Swart van Essen; Bevordering van Volkskracht; Blindenhulp; Landelijke Stichting voor Blinden en Slechtzienden (LSBS); Rotterdamse Vereniging voor Blindenbelangen; OOG Foundation; Algemene Nederlandse Vereniging ter Voorkoming van Blindheid (ANVVB); Rotterdam Eye Institute (REI); Laméris Ootech BV; Topcon BV; Heidelberg Engineering; 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. E.S., A.F.-M. and L.M. were supported by grants from Instituto de Salud Carlos III (ISCIII) (FIS PS09/01979) and Junta de Castilla y León (JcyL) (SA044A08 and GR93) and received institutional support from Red Temática de Investigación Cooperativa en Cáncer (RTICC) (RD06/0020/000), ISCIII, Spain.

The Australian group acknowledges the National Health and Medical Research Council (NHMRC) for the Australian Twin Registry (ATR) Enabling Grant, Project Grant 350415, Medical Genomics Grant, and the Genetic Cluster Computer (NWO 480-05-003), Clifford Craig Medical Research Trust, Ophthalmic Research Institute of Australia (ORIA), American Health Assistance Foundation (AHAF), Peggy and Leslie Cranbourne Foundation, Foundation for Children and Jack Brockhoff Foundation.

The 1958 British Birth Cohort was funded for biomedical assessment (Medical Research Council), for the GWAS (Wellcome Trust 083478) and analysis at Great Ormond Street Hospital/University College London (UCL). Institute of Child Health and Moorfields Eye Hospital/Institute of Ophthalmology, UCL were each part-funded by NIHR Biomedical Research Centres awards.

Additional acknowledgements are contained within the Supplementary Note.

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Contributions

T.L.Y., D.A.M., T.A. and C.J.H. jointly conceived the project and supervised the work. S.M., Y.J.-L., L.Y.F., P.C.S., N.G.M., P.G.H. and A.M.S. helped with the data analyses. A.F.-M., L.M., A.P. and E.S. performed the animal experiments. A.W.H., J.R.V., M.K.I., C.M.v.D., T.D.S., J.S.R. and C.C.W.K. supervised cohort recruitment, genotyping and analysis in replication cohorts. F.C., S.J.F. and M.C.L. contributed during subject and data collection.

Corresponding author

Correspondence to Christopher J Hammond.

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The authors declare no competing financial interests.

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Supplementary Figures 1–5, Supplementary Tables 1–3 and Supplementary Note. (PDF 853 kb)

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Hysi, P., Young, T., Mackey, D. et al. A genome-wide association study for myopia and refractive error identifies a susceptibility locus at 15q25. Nat Genet 42, 902–905 (2010). https://doi.org/10.1038/ng.664

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