Abstract
Macular degeneration is a common cause of blindness in the elderly. To identify rare coding variants associated with a large increase in risk of age-related macular degeneration (AMD), we sequenced 2,335 cases and 789 controls in 10 candidate loci (57 genes). To increase power, we augmented our control set with ancestry-matched exome-sequenced controls. An analysis of coding variation in 2,268 AMD cases and 2,268 ancestry-matched controls identified 2 large-effect rare variants: previously described p.Arg1210Cys encoded in the CFH gene (case frequency (fcase) = 0.51%; control frequency (fcontrol) = 0.02%; odds ratio (OR) = 23.11) and newly identified p.Lys155Gln encoded in the C3 gene (fcase = 1.06%; fcontrol = 0.39%; OR = 2.68). The variants suggest decreased inhibition of C3 by complement factor H, resulting in increased activation of the alternative complement pathway, as a key component of disease biology.
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Acknowledgements
We thank all study participants for their generous volunteering. We thank B. Li, W. Chen, C. Sidore, T. Teslovich, L. Fritsche and M. Boehnke for useful discussion and suggestions. This project was supported by grants from the US National Institutes of Health (National Eye Institute, National Human Genome Research Institute; grants EY022005, HG007022, HG005552, EY016862, U54HG003079 and EY09859); the Medical Research Council, UK (grant G0000067); the Deutsche Forschungsgemeinschaft (grant WE1259/19-2); the Alcon Research Institute; The UK Department of Health's National Institute for Health Research (NIHR) Biomedical Research Centre for Ophthalmology at Moorfields Eye Hospital and the UCL Institute of Ophthalmology; Research to Prevent Blindness (New York); the Thome Memorial Foundation; the Harold and Pauline Price Foundation; and the National Health and Medical Research Council of Australia (NHMRC) Clinical Research Excellence (grant 529923, NHMRC practitioner fellowship 529905 and NHMRC Senior Research Fellowship 1028444). The study was also supported by the Intramural Research Program (Computational Medicine Initiative) of the National Eye Institute. The Centre for Eye Research Australia (CERA) receives operational infrastructure support from the Victorian Government. The views expressed in the publication are those of the authors and not necessarily those of their employers or the funders.
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R.K.W., J.R.H., E.Y.C., D.S., E.R.M., A.S. and G.R.A. conceived, designed and supervised the experiments. X.Z. and G.R.A. wrote the initial version of the manuscript. X.Z., D.E.L., C.W. and D.C.K. analyzed the data. D.E.L., D.C.K., R.S.F., L.L.F. and C.C.F. supervised data generation. C.W. developed statistical methodology. Y.V.S. analyzed protein structures. K.E.B. supervised sample and data collection. J.B.-G., G.J., Y.H., H.M.K. and D.L. contributed data and analysis tools. M.B., R.R. and A.B. assisted in laboratory experiments. M.O. and F.G. carried out experimental studies (genotyping and data analysis) for the Michigan and Regensburg samples, respectively. C.v.S. recruited the family members of sporadic AMD cases and controls and collected peripheral blood samples for the Regensburg study. L.M.O., M.A.P.-V. and J.L.H. provided results and analysis for the Vanderbilt/Miami samples. G.H.S.B., A.H., C.M.v.D. and C.C.W.K. provided results and analysis for samples from the Rotterdam Study, Erasmus Medical Center. V.C., A.T.M., H.S. and J.R.W.Y. provided results and analysis for the Cambridge AMD Study samples. Y.J., Y.P.C., D.E.W. and M.B.G. provided results and analysis for the University of California, Los Angeles/University of Pittsburgh samples. D.J.M., I.K.K., L.A.F. and M.M.D. provided results and analysis for the Utah samples. M.P.J., J.B. and M.L.K. provided results and analysis for the Oregon Health Sciences Center samples. S.C., A.J.R., R.H.G. and P.N.B. provided results and analysis for the University of Melbourne samples. H.L., H.O., M.M.Z. and K.Z. provided results and analysis for the University of California, San Diego samples. C.L. and F.G.P. provided results and analysis for a cohort of individuals with aHUS. B.H.F.W. was involved in the design and planning of the Southern Germany AMD Study. B.H.F.W. participated in study coordination and critically read the manuscript. All authors have critically commented on this manuscript.
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G.R.A., X.Z., C.W. and A.S. are potential beneficiaries of a University of Michigan patent that is now pending that describes association between variant p.Lys155Gln encoded by the complement 3 gene and AMD.
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Zhan, X., Larson, D., Wang, C. et al. Identification of a rare coding variant in complement 3 associated with age-related macular degeneration. Nat Genet 45, 1375–1379 (2013). https://doi.org/10.1038/ng.2758
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DOI: https://doi.org/10.1038/ng.2758
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