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

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

Author information

1
1] Department of Biostatistics, Center for Statistical Genetics, University of Michigan School of Public Health, Ann Arbor, Michigan, USA. [2].

Abstract

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.

PMID:
24036949
PMCID:
PMC3812337
DOI:
10.1038/ng.2758
[Indexed for MEDLINE]
Free PMC Article

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