A rare penetrant mutation in CFH confers high risk of age-related macular degeneration

Two common variants within CFH, the Y402H(1–4) and the rs1410996 SNPs(5,6), explain 17% of age-related macular degeneration (AMD) liability. However, proof for the involvement of CFH, as opposed to a neighboring transcript, and the potential mechanism of susceptibility alleles are lacking. Assuming that rare functional variants might provide mechanistic insights, we used genotype data and high throughput sequencing to discover a rare high-risk CFH haplotype containing an R1210C mutation. This allele has been implicated previously in atypical hemolytic uremic syndrome, and abrogates C-terminal ligand binding(7,8). Genotyping R1210C in 2,423 AMD cases and 1,122 controls demonstrated high penetrance (present in 40 cases versus 1 control, p=7.0×10(−6)) and six year earlier onset of disease (p=2.3×10(−6)). This result suggests that loss of function alleles at CFH likely drive AMD risk. This finding represents one of the first instances where a common complex disease variant has led to discovery of a rare penetrant mutation.