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

Abstract

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 six-fold higher than in the general population, and family-based analysis has resulted in only modestly significant evidence for linkage. In this case-control study drawn from a US-based population of European descent, the authors identified a previously unrecognized common, noncoding variant in complement factor H (CFH), the gene encoding CFH, that substantially increases the influence of this locus on AMD. This study 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, the authors observed purely additive accumulation of risk from alleles at these genes. Additionally, they 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 the study population.—Hans E. Grossniklaus