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


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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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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Authors and Affiliations



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.

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Correspondence to Christopher J Hammond.

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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).

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