Identification of a rare coding variant in complement 3 associated with age-related macular degeneration

Nat Genet. 2013 Nov;45(11):1375-9. doi: 10.1038/ng.2758. Epub 2013 Sep 15.


Macular degeneration is a common cause of blindness in the elderly. To identify rare coding variants associated with a large increase in risk of age-related macular degeneration (AMD), we sequenced 2,335 cases and 789 controls in 10 candidate loci (57 genes). To increase power, we augmented our control set with ancestry-matched exome-sequenced controls. An analysis of coding variation in 2,268 AMD cases and 2,268 ancestry-matched controls identified 2 large-effect rare variants: previously described p.Arg1210Cys encoded in the CFH gene (case frequency (fcase) = 0.51%; control frequency (fcontrol) = 0.02%; odds ratio (OR) = 23.11) and newly identified p.Lys155Gln encoded in the C3 gene (fcase = 1.06%; fcontrol = 0.39%; OR = 2.68). The variants suggest decreased inhibition of C3 by complement factor H, resulting in increased activation of the alternative complement pathway, as a key component of disease biology.

Publication types

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

MeSH terms

  • Aging
  • Complement C3 / genetics*
  • Complement C3 / metabolism
  • Complement Factor H / metabolism
  • Complement Pathway, Alternative / immunology*
  • Gene Frequency
  • Genetic Variation
  • Genotype
  • Macular Degeneration / genetics*
  • Polymorphism, Single Nucleotide


  • CFH protein, human
  • Complement C3
  • Complement Factor H