A rare nonsynonymous sequence variant in C3 is associated with high risk of age-related macular degeneration

Nat Genet. 2013 Nov;45(11):1371-4. doi: 10.1038/ng.2740. Epub 2013 Sep 15.


Through whole-genome sequencing of 2,230 Icelanders, we detected a rare nonsynonymous SNP (minor allele frequency = 0.55%) in the C3 gene encoding a p.Lys155Gln substitution in complement factor 3, which, following imputation into a set of Icelandic cases with age-related macular degeneration (AMD) and controls, associated with disease (odds ratio (OR) = 3.45; P = 1.1 × 10(-7)). This signal is independent of the previously reported common SNPs in C3 encoding p.Pro314Leu and p.Arg102Gly that associate with AMD. The association of p.Lys155Gln was replicated in AMD case-control samples of European ancestry with OR = 4.22 and P = 1.6 × 10(-10), resulting in OR = 3.65 and P = 8.8 × 10(-16) for all studies combined. In vitro studies have suggested that the p.Lys155Gln substitution reduces C3b binding to complement factor H, potentially creating resistance to inhibition by this factor. This resistance to inhibition in turn is predicted to result in enhanced complement activation.

Publication types

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

MeSH terms

  • Amino Acid Substitution
  • Base Sequence
  • Complement Activation / genetics
  • Complement C3 / genetics*
  • Complement C3b / immunology
  • Complement C3b / metabolism*
  • Complement Factor H / immunology
  • Complement Factor H / metabolism
  • Gene Frequency
  • Genetic Predisposition to Disease
  • Genetic Variation
  • Genome-Wide Association Study
  • Genotype
  • Humans
  • Iceland
  • Macular Degeneration / genetics*
  • Polymorphism, Single Nucleotide
  • Risk
  • Sequence Analysis, DNA


  • CFH protein, human
  • Complement C3
  • Complement C3b
  • Complement Factor H