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- Title
A rare penetrant mutation in CFH confers high risk of age-related macular degeneration.
- Authors
Raychaudhuri, Soumya; Iartchouk, Oleg; Chin, Kimberly; Tan, Perciliz L; Tai, Albert K; Ripke, Stephan; Gowrisankar, Sivakumar; Vemuri, Soumya; Montgomery, Kate; Yu, Yi; Reynolds, Robyn; Zack, Donald J; Campochiaro, Betsy; Campochiaro, Peter; Katsanis, Nicholas; Daly, Mark J; Seddon, Johanna M
- Abstract
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.
- Publication
Nature genetics, 2011, Vol 43, Issue 12, p1232
- ISSN
1546-1718
- Publication type
Journal Article
- DOI
10.1038/ng.976