Meta-analysis of 542,934 subjects of European ancestry identifies new genes and mechanisms predisposing to refractive error and myopia

The Consortium for Refractive Error and Myopia, The UK Eye and Vision Consortium, 23andMe Inc.

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Abstract

Refractive errors, in particular myopia, are a leading cause of morbidity and disability worldwide. Genetic investigation can improve understanding of the molecular mechanisms that underlie abnormal eye development and impaired vision. We conducted a meta-analysis of genome-wide association studies (GWAS) that involved 542,934 European participants and identified 336 novel genetic loci associated with refractive error. Collectively, all associated genetic variants explain 18.4% of heritability and improve the accuracy of myopia prediction (area under the curve (AUC) = 0.75). Our results suggest that refractive error is genetically heterogeneous, driven by genes that participate in the development of every anatomical component of the eye. In addition, our analyses suggest that genetic factors controlling circadian rhythm and pigmentation are also involved in the development of myopia and refractive error. These results may enable the prediction of refractive error and the development of personalized myopia prevention strategies in the future.

Original languageEnglish
Pages (from-to)401-407
Number of pages7
JournalNature Genetics
Volume52
Issue number4
DOIs
Publication statusPublished - 1 Apr 2020

Bibliographical note

Funding Information:
P.T.K. and P.J.F oversaw the UK Biobank eye data acquisition with support from the National Institute for Health Research (NIHR), Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology. The UK Biobank Eye and Vision Consortium was supported by grants from UK NIHR (BRC3_026), Moorfields Eye Charity (ST 15 11 E), Fight for Sight (1507/1508), The Macular Society, The International Glaucoma Association (IGA, Ashford UK) and Alcon Research Institute. V.V. is supported by a core UK Medical Research Council (MRC) grant MC_UU_00007/10. 23andMe thanks research participants and employees of 23andMe for making this work possible (a list of contributing staff is available in the Supplementary Note). Genotyping of the GERA cohort was funded by the US National Institute on Aging, the National Institute of Mental Health and the National Institute of Health Common Fund (RC2 AG036607); data analyses were funded by the National Eye Institute (NEI R01 EY027004, E.J.) and the National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK116738, E.J.). The CREAM GWAS meta-analysis was supported by the European Research Council (ERC) under the European Union’s Horizon 2020 Research and Innovation Programme (grant 648268 to C.C.W.K), the Netherlands Organisation for Scientific Research (NWO, 91815655 to C.C.W.K) and the National Eye Institute (R01EY020483). V.J.M.V. acknowledges funding from the Netherlands Organisation for Scientific Research (NWO, grant 91617076). S.M. acknowledges support from the National Health and Medical Research Council (NHMRC) of Australia (grants 1150144, 1116360, 1154543, 1121979). EPIC-Norfolk infrastructure and core functions are supported by the MRC (G1000143) and Cancer Research UK (C864/ A14136). Genotyping was funded by the MRC (MC_PC_13048). A.K.P. is supported by a Moorfields Eye Charity grant. P.J.F. received support from the Richard Desmond Charitable Trust, the National Institute for Health Research to Moorfields Eye Hospital and the Biomedical Research Centre for Ophthalmology. RW and PGH were supported by the National Eye Institute of the National Institutes of Health under award number R21EY029309. M.J.S. is a recipient of a Fight for Sight PhD studentship. K.P. is a recipient of a Fight for Sight PhD studentship. P.G.H. is the recipient of a FfS ECI fellowship. P.G.H. and C.J.H. acknowledge the TFC Frost Charitable Trust Support for the KCL Department of Ophthalmology. Statistical analyses were run in King’s College London on the Rosalind HPC LINUX Clusters and cloud servers. The UK Biobank data were accessed as part of the UK Biobank projects 669 and 17615. J.S.R. is supported in part by the NIHR Biomedical Research Centres at Moorfields Eye Hospital and the UCL Institute of Ophthalmology, and at the UCL Institute of Child Health and Great Ormond Street Hospital, and is an NIHR Senior Investigator. P.M.C. was funded by the Ulverscroft Foundation. O.A.M is supported by Wellcome Trust grant 206619_Z_17_Z and the NIHR Biomedical Research Centre at Moorfields Eye Hospital and the UCL Institute of Ophthalmology.

Publisher Copyright:
© 2020, The Author(s), under exclusive licence to Springer Nature America, Inc.

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