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

• DOI: 10.1038/ng.976
• Publication Date: 2011-10-23T18:16:26Z
• Authors: Soumya Raychaudhuri; Oleg Iartchouk; Kimberly Chin; Perciliz L Tan; Albert K Tai; Stephan Ripke; Sivakumar Gowrisa...; Soumya Vemuri; Kate Montgomery; Yi Yu; Robyn Reynolds; Donald J Zack; Betsy Campochiaro; Peter Campochiaro; Nicholas Katsanis; Mark J Daly; Johanna M Seddon
• Keywords: Aged, 80 and over; Male; Heterozygote; Principal Component Analysis; 0303 health sciences; Mutation, Missense; High-Throughput Nucleotide Sequencing; Penetrance; Sequence Analysis, DNA; Middle Aged; Polymorphism, Single Nucleotide; Article; Linkage Disequilibrium; Macular Degeneration; 03 medical and health sciences; Haplotypes; Risk Factors; Case-Control Studies; Complement Factor H; Humans; Female; Genetic Predisposition to Disease; Aged

Two common variants in the gene encoding complement factor H (CFH), the Y402H substitution (rs1061170, c.1204C>T)(1-4) and the intronic rs1410996 SNP(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 knowledge of 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 with a c.3628C>T mutation that resulted in an R1210C substitution. This allele has been implicated previously in atypical hemolytic uremic syndrome, and it 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 an association with a 6-year-earlier onset of disease (P = 2.3 × 10(-6)). This result suggests that loss-of-function alleles at CFH are likely to drive AMD risk. This finding represents one of the first instances in which a common complex disease variant has led to the discovery of a rare penetrant mutation.