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.
Maller
Julian
J
Center for Human Genetic Research, Massachusetts General Hospital, 185 Cambridge St., Boston, Massachusetts 02114, USA.
George
Sarah
S
Purcell
Shaun
S
Fagerness
Jes
J
Altshuler
David
D
Daly
Mark J
MJ
Seddon
Johanna M
JM
D000368:Aged; D000483:Alleles; D016022:Case-Control Studies; D016009:Chi-Square Distribution; D017242:Complement Factor H / Q000235:genetics*; D014644:Genetic Variation; D006801:Humans; D016015:Logistic Models; D008268:Macular Degeneration / Q000235:genetics* / Q000473:pathology; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D035781:Siblings; D014481:United States / Q000453:epidemiology; D044465:White People
D017242:Complement Factor H