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

Published online

Journal Article

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.

Full Text

Cited Authors

  • Raychaudhuri, S; Iartchouk, O; Chin, K; Tan, PL; Tai, AK; Ripke, S; Gowrisankar, S; Vemuri, S; Montgomery, K; Yu, Y; Reynolds, R; Zack, DJ; Campochiaro, B; Campochiaro, P; Katsanis, N; Daly, MJ; Seddon, JM

Published Date

  • October 23, 2011

Published In

Volume / Issue

  • 43 / 12

Start / End Page

  • 1232 - 1236

PubMed ID

  • 22019782

Pubmed Central ID

  • 22019782

Electronic International Standard Serial Number (EISSN)

  • 1546-1718

Digital Object Identifier (DOI)

  • 10.1038/ng.976


  • eng

Conference Location

  • United States