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


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.

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Figure 1: P values for single-SNP association, when comparing unrelated affected individuals (cases) and controls.


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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



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)

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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).

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