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.

A rare nonsynonymous sequence variant in C3 is associated with high risk of age-related macular degeneration

Abstract

Through whole-genome sequencing of 2,230 Icelanders, we detected a rare nonsynonymous SNP (minor allele frequency = 0.55%) in the C3 gene encoding a p.Lys155Gln substitution in complement factor 3, which, following imputation into a set of Icelandic cases with age-related macular degeneration (AMD) and controls, associated with disease (odds ratio (OR) = 3.45; P = 1.1 × 10−7). This signal is independent of the previously reported common SNPs in C3 encoding p.Pro314Leu and p.Arg102Gly that associate with AMD. The association of p.Lys155Gln was replicated in AMD case-control samples of European ancestry with OR = 4.22 and P = 1.6 × 10−10, resulting in OR = 3.65 and P = 8.8 × 10−16 for all studies combined. In vitro studies have suggested that the p.Lys155Gln substitution reduces C3b binding to complement factor H, potentially creating resistance to inhibition by this factor. This resistance to inhibition in turn is predicted to result in enhanced complement activation.

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

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: Overview of the association in the C3 gene region.

Accession codes

Accessions

NCBI Reference Sequence

References

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

    Article  PubMed  Google Scholar 

  2. Hindorff, L.A. et al. Potential etiologic and functional implications of genome-wide association loci for human diseases and traits. Proc. Natl. Acad. Sci. USA 106, 9362–9367 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Maller, J. et al. Common variation in three genes, including a noncoding variant in CFH, strongly influences risk of age-related macular degeneration. Nat. Genet. 38, 1055–1059 (2006).

    Article  CAS  PubMed  Google Scholar 

  4. 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 

  5. 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 

  6. Raychaudhuri, S. et al. Associations of CFHR1-CFHR3 deletion and a CFH SNP to age-related macular degeneration are not independent. Nat. Genet. 42, 553–555 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Zhan, X. et al. Targeted sequencing, augmented with public resources, identifies a rare complement 3 allele associated with AMD. Nat. Genet. 10.1038/ng.2578 (15 September 2013).

  10. Wu, J. et al. Structure of complement fragment C3b–factor H and implications for host protection by complement regulators. Nat. Immunol. 10, 728–733 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Miller, E. Characterization of Complement C3 Dysregulation Predisposing to Two Human Disease States, PhD thesis, Washington University (2012).

  12. Kiemeney, L.A. et al. Sequence variant on 8q24 confers susceptibility to urinary bladder cancer. Nat. Genet. 40, 1307–1312 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Bird, A.C. et al. An international classification and grading system for age-related maculopathy and age-related macular degeneration. The International ARM Epidemiological Study Group. Surv. Ophthalmol. 39, 367–374 (1995).

    Article  CAS  PubMed  Google Scholar 

  14. van Leeuwen, R. et al. Grading of age-related maculopathy for epidemiological studies: is digital imaging as good as 35-mm film? Ophthalmology 110, 1540–1544 (2003).

    Article  PubMed  Google Scholar 

  15. Kutyavin, I.V. et al. A novel endonuclease IV post-PCR genotyping system. Nucleic Acids Res. 34, e128 (2006).

    Article  PubMed  PubMed Central  Google Scholar 

  16. Yang, Z. et al. A variant of the HTRA1 gene increases susceptibility to age-related macular degeneration. Science 314, 992–993 (2006).

    Article  CAS  PubMed  Google Scholar 

  17. 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 

  18. 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 

  19. DePristo, M.A. et al. A framework for variation discovery and genotyping using next-generation DNA sequencing data. Nat. Genet. 43, 491–498 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Cingolani, P. et al. A program for annotating and predicting the effects of single nucleotide polymorphisms, SnpEff: SNPs in the genome of Drosophila melanogaster strain w1118; iso-2; iso-3. Fly (Austin) 6, 80–92 (2012).

    Article  CAS  Google Scholar 

  21. Kong, A. et al. Detection of sharing by descent, long-range phasing and haplotype imputation. Nat. Genet. 40, 1068–1075 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Kong, A. et al. Parental origin of sequence variants associated with complex diseases. Nature 462, 868–874 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Marchini, J., Howie, B., Myers, S., McVean, G. & Donnelly, P. A new multipoint method for genome-wide association studies by imputation of genotypes. Nat. Genet. 39, 906–913 (2007).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors would like to thank the individuals who participated in the study and whose contributions made this work possible. We thank our valued colleagues who contributed to data collection, sample handling, genotyping and data analysis. H.L., Y.D. and K.Z. are supported in part by 973 program grant 2013CB967504, National Science Foundation of China grant 81130017, the NEI/US National Institutes of Health and a Veterans Affairs Merit Award. The Dutch replication study was supported by the Netherlands Organization for Scientific Research (Vidi Innovational Research Award 016.096.309 to A.I.d.H.) and the Foundation Fighting Blindness (grant C-GE-0811-0548-RAD04 to A.I.d.H.).

Author information

Authors and Affiliations

Authors

Contributions

The study was designed and results interpreted by H.H., P.S., H. Stefansson, G.T., U.T. and K.S. H.H., P.S. and U.T. wrote the first draft and, together with I.J., D.F.G. and K.S. wrote the final version of the manuscript. Statistical analysis was carried out by H.H., P.S., G.T., D.F.G. and A.K. O.T.M. oversaw sequencing for the Icelandic cohort, and G.M. processed the raw sequencing data. Subject recruitment, phenotyping, biological material collection and handling, and genotyping were supervised and carried out by H. Stefansson, G.T., G.B.W., T. Rafnar, A.G., G.H., E.S., F.J., H. Sigurdsson, A.I.d.H., M.R.D., F.E.S.-K., C.J.F.B., S.F., T. Ristau, S.L., J.P.H.v.d.V., C.B.H., K.Z., H.L., L.Z., Y.S., M.P., S.P., H.F., Y.D. and P.S.B. Principal investigators and corresponding authors for the replication study populations are A.I.d.H. (the EUGENDA cohort), K.Z. (the US cohort) and L.A.K. (population controls from Nijmegen).

Corresponding authors

Correspondence to Patrick Sulem or Kari Stefansson.

Ethics declarations

Competing interests

The authors declare competing financial interests. H.H., P.S., G.T., H. Stefansson, I.J., G.M., D.F.G., G.B.W., O.T.M., A.K., T.R., U.T. and K.S. are employees of deCODE Genetics/Amgen.

Supplementary information

Supplementary Text and Figures

Supplementary Figure 1 and Supplementary Tables 1–12 (PDF 848 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Helgason, H., Sulem, P., Duvvari, M. et al. A rare nonsynonymous sequence variant in C3 is associated with high risk of age-related macular degeneration. Nat Genet 45, 1371–1374 (2013). https://doi.org/10.1038/ng.2740

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng.2740

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing