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Common variation in three genes, including a noncoding variant in CFH, strongly influences risk of age-related macular degeneration


Age-related macular degeneration (AMD) is a common, late-onset disease with seemingly typical complexity: recurrence ratios for siblings of an affected individual are three- to sixfold higher than in the general population, and family-based analysis has resulted in only modestly significant evidence for linkage. In a case-control study drawn from a US-based population of European descent, we have identified a previously unrecognized common, noncoding variant in CFH, the gene encoding complement factor H, that substantially increases the influence of this locus on AMD, and we have strongly replicated the associations of four other previously reported common alleles in three genes (P values ranging from 10−6 to 10−70). Despite excellent power to detect epistasis, we observed purely additive accumulation of risk from alleles at these genes. We found no differences in association of these loci with major phenotypic categories of advanced AMD. Genotypes at these five common SNPs define a broad spectrum of interindividual disease risk and explain about half of the classical sibling risk of AMD in our study population.

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Figure 1: Relative risk plotted as a function of the genetic load of the five variants that influence risk of AMD.


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We thank the study participants, their families and numerous ophthalmologists throughout the country who participated in this study. We particularly thank D. Mirel and the NCRR Broad Institute Center for Genotyping and Analysis for expert design and execution of the SNP genotyping reported herein, and P. de Bakker for comments and Figure 1 graphics. We also thank AREDS participants and investigators and the EMMES Corporation for their work on the AREDS Genetic Repository. This research was supported by EY11309 from the US National Institutes of Health; the Foundation Fighting Blindness; Massachusetts Lions Research Fund, Inc.; the Epidemiology Unit AMD Genetics Research Fund, Massachusetts Eye and Ear Infirmary; and the Broad Institute Center for Genotyping and Analysis, supported by grant U54 RR020278 from the NCRR.

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Corresponding authors

Correspondence to Mark J Daly or Johanna M Seddon.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Phylogenetic tree of CEU Phase II HapMap data (release 20) of the region containing the associated alleles at BF/C2. (PDF 12 kb)

Supplementary Table 1

Illustration of conditional tests. (PDF 13 kb)

Supplementary Table 2

Model selection for the CFH, LOC387715, and multi-locus model. (PDF 17 kb)

Supplementary Table 3

Association of SNPs in CFH region. (PDF 17 kb)

Supplementary Table 4

Association of SNPs and haplotypes in LOC387715 region. (PDF 14 kb)

Supplementary Table 5

Multi-locus risk model. (PDF 39 kb)

Supplementary Table 6

Risk model with estimated HapMap CEU frequencies. (PDF 56 kb)

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Maller, J., George, S., Purcell, S. 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).

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