Nature Genetics
- 38, 1055 - 1059 (2006)
Published online: 27 August 2006; | doi:10.1038/ng1873
Common variation in three genes, including a noncoding variant in CFH, strongly influences risk of age-related macular degenerationJulian Maller1, 3, Sarah George2, Shaun Purcell1, 3, Jes Fagerness1, 3, David Altshuler1, 3, 4, Mark J Daly1, 3, 4 & Johanna M Seddon2, 41
Center for Human Genetic Research, Massachusetts General Hospital, 185 Cambridge St., Boston, Massachusetts 02114, USA. 2
Epidemiology Unit, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, 243 Charles St. Boston, Massachusetts 02114, USA. 3
Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA. 4
Harvard Medical School, Boston, Massachusetts, USA.
Correspondence should be addressed to Johanna M Seddon johanna_seddon@meei.harvard.edu or Mark J Daly mjdaly@chgr.mgh.harvard.edu 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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