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.

CFH haplotypes without the Y402H coding variant show strong association with susceptibility to age-related macular degeneration

Abstract

In developed countries, age-related macular degeneration is a common cause of blindness in the elderly. A common polymorphism, encoding the sequence variation Y402H in complement factor H (CFH), has been strongly associated with disease susceptibility. Here, we examined 84 polymorphisms in and around CFH in 726 affected individuals (including 544 unrelated individuals) and 268 unrelated controls. In this sample, 20 of these polymorphisms showed stronger association with disease susceptibility than the Y402H variant. Further, no single polymorphism could account for the contribution of the CFH locus to disease susceptibility. Instead, multiple polymorphisms defined a set of four common haplotypes (of which two were associated with disease susceptibility and two seemed to be protective) and multiple rare haplotypes (associated with increased susceptibility in aggregate). Our results suggest that there are multiple disease susceptibility alleles in the region and that noncoding CFH variants play a role in disease susceptibility.

Your institute does not have access to this article

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: P values for single-SNP association, when comparing unrelated affected individuals (cases) and controls.

References

  1. Majewski, J. et al. Age-related macular degeneration–a genome scan in extended families. Am. J. Hum. Genet. 73, 540–550 (2003).

    CAS  Article  Google Scholar 

  2. Abecasis, G.R. et al. Age-related macular degeneration: a high-resolution genome scan for susceptibility loci in a population enriched for late-stage disease. Am. J. Hum. Genet. 74, 482–494 (2004).

    CAS  Article  Google Scholar 

  3. Weeks, D.E. et al. Age-related maculopathy: an expanded genome-wide scan with evidence of susceptibility loci within the 1q31 and 17q25 regions. Am. J. Ophthalmol. 132, 682–692 (2001).

    CAS  Article  Google Scholar 

  4. Seddon, J.M., Santangelo, S.L., Book, K., Chong, S. & Cote, J. A genomewide scan for age-related macular degeneration provides evidence for linkage to several chromosomal regions. Am. J. Hum. Genet. 73, 780–790 (2003).

    CAS  Article  Google Scholar 

  5. Fisher, S.A. et al. Meta-analysis of genome scans of age-related macular degeneration. Hum. Mol. Genet. 14, 2257–2264 (2005).

    CAS  Article  Google Scholar 

  6. Hirvela, H., Luukinen, H., Laara, E., Sc, L. & Laatikainen, L. Risk factors of age-related maculopathy in a population 70 years of age or older. Ophthalmology 103, 871–877 (1996).

    CAS  Article  Google Scholar 

  7. Smith, W. et al. Risk factors for age-related macular degeneration: Pooled findings from three continents. Ophthalmology 108, 697–704 (2001).

    CAS  Article  Google Scholar 

  8. Klein, R., Klein, B.E., Tomany, S.C. & Moss, S.E. Ten-year incidence of age-related maculopathy and smoking and drinking: the Beaver Dam Eye Study. Am. J. Epidemiol. 156, 589–598 (2002).

    Article  Google Scholar 

  9. Schmidt, S. et al. Cigarette smoking strongly modifies the association of LOC387715 and age-related macular degeneration. Am. J. Hum. Genet. 78, 852–864 (2006).

    CAS  Article  Google Scholar 

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

    CAS  Article  Google Scholar 

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

    CAS  Article  Google Scholar 

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

    CAS  Article  Google Scholar 

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

    CAS  Article  Google Scholar 

  14. 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).

    CAS  Article  Google Scholar 

  15. Zareparsi, S. et al. Strong association of the Y402H variant in complement factor H at 1q32 with susceptibility to age-related macular degeneration. Am. J. Hum. Genet. 77, 149–153 (2005).

    CAS  Article  Google Scholar 

  16. Li, M., Boehnke, M. & Abecasis, G.R. Joint modeling of linkage and association: identifying SNPs responsible for a linkage signal. Am. J. Hum. Genet. 76, 934–949 (2005).

    CAS  Article  Google Scholar 

  17. Li, M., Boehnke, M. & Abecasis, G.R. Efficient study designs for test of genetic association using sibship data and unrelated cases and controls. Am. J. Hum. Genet. 78, 778–792 (2006).

    CAS  Article  Google Scholar 

  18. Risch, N. Linkage strategies for genetically complex traits. I. Multilocus models. Am. J. Hum. Genet. 46, 222–228 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Hodge, S.E. & Elston, R.C. Lods, wrods, and mods: the interpretation of lod scores calculated under different models. Genet. Epidemiol. 11, 329–342 (1994).

    CAS  Article  Google Scholar 

  20. Valdes, A.M. & Thomson, G. Detecting disease-predisposing variants: the haplotype method. Am. J. Hum. Genet. 60, 703–716 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Zaykin, D.V. et al. Testing association of statistically inferred haplotypes with discrete and continuous traits in samples of unrelated individuals. Hum. Hered. 53, 79–91 (2002).

    Article  Google Scholar 

  22. Stephens, M., Smith, N.J. & Donnelly, P. A new statistical method for haplotype reconstruction from population data. Am. J. Hum. Genet. 68, 978–989 (2001).

    CAS  Article  Google Scholar 

  23. Li, N. & Stephens, M. Modeling linkage disequilibrium and identifying recombination hotspots using single-nucleotide polymorphism data. Genetics 165, 2213–2233 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. The International HapMap Consortium. The International HapMap Project. Nature 437, 1299–1320 (2005).

  25. Monks, S.A. et al. Genetic inheritance of gene expression in human cell lines. Am. J. Hum. Genet. 75, 1094–1105 (2004).

    CAS  Article  Google Scholar 

  26. 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).

    CAS  Article  Google Scholar 

  27. Wigginton, J.E., Cutler, D.J. & Abecasis, G.R. A note on exact tests of Hardy-Weinberg equilibrium. Am. J. Hum. Genet. 76, 887–883 (2005).

    CAS  Article  Google Scholar 

  28. Abecasis, G.R., Martin, R. & Lewitzky, S. Estimation of haplotype frequencies from diploid data. Am. J. Hum. Genet. 69, S198 (2001).

    Article  Google Scholar 

  29. Abecasis, G.R. & Cookson, W.O.C. GOLD—graphical overview of linkage disequilibrium. Bioinformatics 16, 182–183 (2000).

    CAS  Article  Google Scholar 

  30. Stephens, M. & Scheet, P. Accounting for decay of linkage disequilibrium in haplotype inference and missing-data imputation. Am. J. Hum. Genet. 76, 449–462 (2005).

    CAS  Article  Google Scholar 

Download references

Acknowledgements

We acknowledge the participation of members of AMD-affected families and of numerous clinicians and clinical staff members, without whose generous assistance and dedication this work would not be possible. We also thank M. Boehnke and R. Spielman for comments on early versions of the manuscript, S. Gabriel and L. Ziagra at the Broad Institute/National Center for Research Resources Genotyping Center for generating the genotype data and for stimulating discussions, R. Lyons at the University of Michigan Sequencing facility for help with DNA sequencing and S. Ferrara for administrative support. This research was supported by grants from the US National Institutes of Health, The Foundation Fighting Blindness, the Elmer and Sylvia Sramek Foundation and Research to Prevent Blindness (RPB). A.S. is Harold F. Falls Collegiate Professor and a recipient of an RPB Senior Scientific Investigator award. G.R.A. is a Pew Scholar for the Biomedical Sciences. P.A.-S. was supported in part by a scholarship from TUBITAK.

Author information

Authors and Affiliations

Authors

Contributions

M.L., Y.L. and L.L. carried out the statistical analyses. P.A.-S., M.O., K.E.H.-B., R.K.M.S.W. and S.Z. were responsible for execution of experiments and for sample preparation and collection. A.S. and G.R.A. conceived and directed the study.

Corresponding authors

Correspondence to Anand Swaroop or Gonçalo R Abecasis.

Supplementary information

Supplementary Fig. 1

Analysis of Y402H and of SNPs selected in our stepwise search using the haplotype method of Valdes and Thomson (1997). (PDF 430 kb)

Supplementary Fig. 2

Sensitivity of LAMP results to estimates of disease prevalence. (PDF 80 kb)

Supplementary Table 1

Association test results for all SNPs. (PDF 112 kb)

Supplementary Table 2

Genotype counts and allelic and genotypic association test results for all 84 SNPs. (PDF 21 kb)

Supplementary Table 3

Genotype counts and mean allelic and genotypic test results in the 10 imputed datasets. (PDF 19 kb)

Supplementary Table 4

Results using alternative approaches for SNP selection. (PDF 11 kb)

Supplementary Table 5

Results of exhaustive search for the best SNP combination. (PDF 12 kb)

Supplementary Table 6

Haplo-genotype counts for cases and controls. (PDF 11 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Li, M., Atmaca-Sonmez, P., Othman, M. et al. CFH haplotypes without the Y402H coding variant show strong association with susceptibility to age-related macular degeneration. Nat Genet 38, 1049–1054 (2006). https://doi.org/10.1038/ng1871

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng1871

Further reading

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