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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Seddon, J.M. et al. A genomewide scan for age-related macular degenerations providences evidence for linkage to several chromosomal regions. Am. J. Hum. Genet. 73, 780–790 (2003).
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).
Majewski, J. et al. Age-related macular degeneration—a genome scan in extended families. Am. J. Hum. Genet. 73, 540–550 (2003).
Iyengar, S.K. et al. Dissection of genomewide-scan data in extended families reveals a major locus and oligogenic susceptibility for age-related macular degeneration. Am. J. Hum. Genet. 74, 20–39 (2004).
Klein, R.J. et al. Complement factor H polymorphism in age-related macular degeneration. Science 308, 385–389 (2005).
Edwards, A.O. et al. Complement factor H polymorphism and age-related macular degeneration. Science 308, 421–424 (2005).
Hageman, G.S. et al. A common haplotype in the complement regulatory gene factor H (HF1/CFH) predisposes individuals to age-related macular degeneration. Proc. Natl. Acad. Sci. USA 102, 7227–7232 (2005).
Haines, J.L. et al. Complement Factor H variant increases the risk of age-related macular degeneration. Science 308, 419–421 (2005).
Seddon, J.M., Sharma, S. & Adelman, R.A. Evaluation of the clinical age-related maculopathy staging system. Ophthalmology 113, 260–266 (2006).
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).
Jakobsdottir, J. et al. Susceptibility genes for age-related maculopathy on chromosome 10q26. Am. J. Hum. Genet. 77, 389–407 (2005).
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).
Seddon, J.M., Ajani, U.A. & Mitchell, B.D. Familial aggregation of age-related maculopathy. Am. J. Ophthalmol. 123, 199–206 (1997).
Heiba, I.M., Elston, R.C., Klein, B.E. & Klein, R. Sibling correlations and segregation analysis of age-related maculopathy: the Beaver Dam Eye Study. Genet. Epidemiol. 11, 51–67 (1994).
Klaver, C.C. et al. Genetic risk of age-related maculopathy. Population-based familial aggregation study. Arch. Ophthalmol. 116, 1646–1651 (1997).
Seddon, J., George, S., Rosner, B. & Klein, M. CFH gene variant, Y402H, and smoking, body mass index, environmental associations with advanced age-related macular degeneration. Hum. Hered. 61, 157–165 (2006).
Fisher, R.A. The correlation between relatives on the supposition of Mendelian inheritance. Trans. R. Soc. Edinburgh. 52, 399–433 (1918).
Age-Related Eye Disease Study Research Group. A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C & E, beta carotene, and zinc for age-related macular degeneration and vision loss. Arch. Ophthalmol. 119, 1417–1436 (2001).
Seddon, J.M., Cote, J., Davis, N. & Rosner, B. Progression of age-related macular degeneration: Association with body mass index, waist circumference and waist-hip ratio. Arch. Ophthalmol. 121, 785–792 (2003).
Seddon, J.M., Cote, J., Davis, N. & Rosner, B. Progression of age-related macular degeneration: association with dietary fat, transunsaturated fat, nuts, and fish intake. Arch. Ophthalmol. 121, 1728–1737 (2003).
Snow, K.K. et al. Association between reproductive factors and age-related maculopathy in post-menopausal women. Am. J. Ophthalmol. 134, 842–848 (2002).
Seddon, J.M., Cote, J., Page, W.F., Aggen, S. & Neale, M. The US twin study of age-related macular degeneration: relative roles of genetic and environmental influences. Arch. Ophthalmol. 123, 321–327 (2005).
Fisher, S.A. et al. Meta-analysis of genome scans of age-related macular degeneration. Hum. Mol. Genet. 14, 2257–2264 (2005).
Haddad, S., Chen, C., Santangelo, S.L. & Seddon, J.M. The genetics of age-related macular degeneration: a review of progress to date. Surv. Ophthalmol. 51, 316–363 (2006).
Sham, P.C. et al. Haplotype association analysis of discrete and continuous traits using mixture of regression models. Behav. Genet. 34, 207–214 (2004).
Cordell, H.J. Estimation and testing of genotype and haplotype effects in case-control studies: comparison of weighted regression and multiple imputation procedures. Genet. Epidemiol. 30, 259–275 (2006).
Risch, N. & Merikangas, K. The future of genetic studies of complex human diseases. Science 273, 1516–1517 (1996).
Devlin, B. & Roeder, K. Genomic control for association studies. Biometrics 55, 997–1004 (1999).
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.
The authors declare no competing financial interests.
Phylogenetic tree of CEU Phase II HapMap data (release 20) of the region containing the associated alleles at BF/C2. (PDF 12 kb)
Illustration of conditional tests. (PDF 13 kb)
Model selection for the CFH, LOC387715, and multi-locus model. (PDF 17 kb)
Association of SNPs in CFH region. (PDF 17 kb)
Association of SNPs and haplotypes in LOC387715 region. (PDF 14 kb)
Multi-locus risk model. (PDF 39 kb)
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) doi:10.1038/ng1873
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