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

Nat Genet. 2011 Oct 23;43(12):1232-6. doi: 10.1038/ng.976.

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 types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Case-Control Studies
  • Complement Factor H / genetics
  • Female
  • Genetic Predisposition to Disease*
  • Haplotypes
  • Heterozygote
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Linkage Disequilibrium
  • Macular Degeneration / genetics*
  • Macular Degeneration / pathology
  • Male
  • Middle Aged
  • Mutation, Missense
  • Penetrance*
  • Polymorphism, Single Nucleotide
  • Principal Component Analysis
  • Risk Factors
  • Sequence Analysis, DNA

Substances

  • CFH protein, human
  • Complement Factor H