Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Identification of a rare coding variant in complement 3 associated with age-related macular degeneration

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.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: C3 variants p. Arg102Gly and p.Lys155Gln and CFH variant p.Arg1210Cys are in the interaction domains of the first α-macroglobular domains of C3b and CFH, respectively.

Similar content being viewed by others

Accession codes

Accessions

Protein Data Bank

References

  1. Priya, R.R., Chew, E.Y. & Swaroop, A. Genetic studies of age-related macular degeneration: lessons, challenges, and opportunities for disease management. Ophthalmology 119, 2526–2536 (2012).

    Article  PubMed  Google Scholar 

  2. Swaroop, A., Chew, E.Y., Rickman, C.B. & Abecasis, G.R. Unraveling a multifactorial late-onset disease: from genetic susceptibility to disease mechanisms for age-related macular degeneration. Annu. Rev. Genomics Hum. Genet. 10, 19–43 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Friedman, D.S. et al. Prevalence of age-related macular degeneration in the United States. Arch. Ophthalmol. 122, 564–572 (2004).

    PubMed  Google Scholar 

  4. Haines, J.L. et al. Complement factor H variant increases the risk of age-related macular degeneration. Science 308, 419–421 (2005).

    Article  CAS  PubMed  Google Scholar 

  5. Edwards, A.O. et al. Complement factor H polymorphism and age-related macular degeneration. Science 308, 421–424 (2005).

    Article  CAS  PubMed  Google Scholar 

  6. Klein, R.J. et al. Complement factor H polymorphism in age-related macular degeneration. Science 308, 385–389 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Jakobsdottir, J. et al. Susceptibility genes for age-related maculopathy on chromosome 10q26. Am. J. Hum. Genet. 77, 389–407 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Rivera, A. et al. Hypothetical LOC387715 is a second major susceptibility gene for age-related macular degeneration, contributing independently of complement factor H to disease risk. Hum. Mol. Genet. 14, 3227–3236 (2005).

    Article  CAS  PubMed  Google Scholar 

  9. Yates, J.R. et al. Complement C3 variant and the risk of age-related macular degeneration. N. Engl. J. Med. 357, 553–561 (2007).

    Article  CAS  PubMed  Google Scholar 

  10. Gold, B. et al. Variation in factor B (BF) and complement component 2 (C2) genes is associated with age-related macular degeneration. Nat. Genet. 38, 458–462 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Fagerness, J.A. et al. Variation near complement factor I is associated with risk of advanced AMD. Eur. J. Hum. Genet. 17, 100–104 (2009).

    Article  CAS  PubMed  Google Scholar 

  12. Maller, J.B. et al. Variation in complement factor 3 is associated with risk of age-related macular degeneration. Nat. Genet. 39, 1200–1201 (2007).

    Article  CAS  PubMed  Google Scholar 

  13. Fritsche, L.G. et al. Seven new loci associated with age-related macular degeneration. Nat. Genet. 45, 433–439 (2013).

    Article  CAS  PubMed  Google Scholar 

  14. Arakawa, S. et al. Genome-wide association study identifies two susceptibility loci for exudative age-related macular degeneration in the Japanese population. Nat. Genet. 43, 1001–1004 (2011).

    Article  CAS  PubMed  Google Scholar 

  15. Nejentsev, S., Walker, N., Riches, D., Egholm, M. & Todd, J.A. Rare variants of IFIH1, a gene implicated in antiviral responses, protect against type 1 diabetes. Science 324, 387–389 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Raychaudhuri, S. et al. A rare penetrant mutation in CFH confers high risk of age-related macular degeneration. Nat. Genet. 43, 1232–1236 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Józsi, M. et al. Factor H and atypical hemolytic uremic syndrome: mutations in the C-terminus cause structural changes and defective recognition functions. J. Am. Soc. Nephrol. 17, 170–177 (2006).

    Article  PubMed  Google Scholar 

  18. Manuelian, T. et al. Mutations in factor H reduce binding affinity to C3b and heparin and surface attachment to endothelial cells in hemolytic uremic syndrome. J. Clin. Invest. 111, 1181–1190 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Ferreira, V.P. et al. The binding of factor H to a complex of physiological polyanions and C3b on cells is impaired in atypical hemolytic uremic syndrome. J. Immunol. 182, 7009–7018 (2009).

    Article  CAS  PubMed  Google Scholar 

  20. Chen, W. et al. Genetic variants near TIMP3 and high-density lipoprotein–associated loci influence susceptibility to age-related macular degeneration. Proc. Natl. Acad. Sci. USA 107, 7401–7406 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Age-Related Eye Disease Study Research Group. Risk factors associated with age-related macular degeneration. A case-control study in the age-related eye disease study: Age-Related Eye Disease Study Report Number 3. Ophthalmology 107, 2224–2232 (2000).

  22. Tennessen, J.A. et al. Evolution and functional impact of rare coding variation from deep sequencing of human exomes. Science 337, 64–69 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Fu, W. et al. Analysis of 6,515 exomes reveals the recent origin of most human protein-coding variants. Nature 493, 216–220 (2013).

    Article  CAS  PubMed  Google Scholar 

  24. 1000 Genomes Project Consortium. An integrated map of genetic variation from 1,092 human genomes. Nature 491, 56–65 (2012).

  25. Mathieson, I. & McVean, G. Differential confounding of rare and common variants in spatially structured populations. Nat. Genet. 44, 243–246 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Li, J.Z. et al. Worldwide human relationships inferred from genome-wide patterns of variation. Science 319, 1100–1104 (2008).

    Article  CAS  PubMed  Google Scholar 

  27. Wellcome Trust Case Control Consortium. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447, 661–678 (2007).

  28. Li, B. & Leal, S.M. Methods for detecting associations with rare variants for common diseases: application to analysis of sequence data. Am. J. Hum. Genet. 83, 311–321 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Price, A.L. et al. Pooled association tests for rare variants in exon-resequencing studies. Am. J. Hum. Genet. 86, 832–838 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  30. Wu, M.C. et al. Rare-variant association testing for sequencing data with the sequence kernel association test. Am. J. Hum. Genet. 89, 82–93 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Helgason, H. et al. A rare nonsynonymous sequence variant in C3 confers high risk of age-related macular degeneration. Nat. Genet. 10.1038/ng.2740 (15 September 2013).

  32. AREDS2 Research Group. et al. The Age-Related Eye Disease Study 2 (AREDS2): study design and baseline characteristics (AREDS2 report number 1). Ophthalmology 119, 2282–2289 (2012).

  33. Heurich, M. et al. Common polymorphisms in C3, factor B, and factor H collaborate to determine systemic complement activity and disease risk. Proc. Natl. Acad. Sci. USA 108, 8761–8766 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Fritsche, L.G. et al. Age-related macular degeneration is associated with an unstable ARMS2 (LOC387715) mRNA. Nat. Genet. 40, 892–896 (2008).

    Article  CAS  PubMed  Google Scholar 

  35. Kanda, A. et al. A variant of mitochondrial protein LOC387715/ARMS2, not HTRA1, is strongly associated with age-related macular degeneration. Proc. Natl. Acad. Sci. USA 104, 16227–16232 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Dewan, A. et al. HTRA1 promoter polymorphism in wet age-related macular degeneration. Science 314, 989–992 (2006).

    Article  CAS  PubMed  Google Scholar 

  37. Sánchez-Corral, P. et al. Structural and functional characterization of factor H mutations associated with atypical hemolytic uremic syndrome. Am. J. Hum. Genet. 71, 1285–1295 (2002).

    Article  PubMed  PubMed Central  Google Scholar 

  38. Li, H. & Durbin, R. Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics 25, 1754–1760 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. McKenna, A. et al. The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res. 20, 1297–1303 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Jun, G. et al. Detecting and estimating contamination of human DNA samples in sequencing and array-based genotype data. Am. J. Hum. Genet. 91, 839–848 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Cox, D.R. & Shell, E.J. Analysis of Binary Data 2nd edn. (CRC Press, New York, 1989).

  42. Hirji, K.F., Mehta, C.R. & Patel, N.R. Computing distributions for exact logistic-regression. J. Am. Stat. Assoc. 82, 1110–1117 (1987).

    Article  Google Scholar 

  43. Rosenbaum, P.R. & Rubin, D.B. The central role of the propensity score in observational studies for causal effects. Biometrika 70, 41–55 (1983).

    Article  Google Scholar 

Download references

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.

Author information

Authors and Affiliations

Authors

Contributions

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.

Corresponding author

Correspondence to Goncalo R Abecasis.

Ethics declarations

Competing interests

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.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–5 and Supplementary Tables 1–6 (PDF 1553 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng.2758

This article is cited by

Search

Quick links

Nature Briefing: Translational Research

Sign up for the Nature Briefing: Translational Research newsletter — top stories in biotechnology, drug discovery and pharma.

Get what matters in translational research, free to your inbox weekly. Sign up for Nature Briefing: Translational Research