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Nature Research, Nature Genetics, 11(45), p. 1375-1379, 2013

DOI: 10.1038/ng.2758

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Identification of a Rare Coding Variant in Complement 3 Associated with Age-related Macular Degeneration

Journal article published in 2013 by Xiaowei Zhan, David E. Larson, Chaolong Wang, Daniel C. Koboldt, Yuri V. Sergeev, Robert S. Fulton, Lucinda Ll Fulton, Catrina Cc Fronick, Kari E. Branham, Jennifer Bragg-Gresham, Goo Jun, Youna Hu, Hyun Min Kang, Dajiang Liu, Mohammad Othman and other authors.
This paper is made freely available by the publisher.
This paper is made freely available by the publisher.

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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 (f case) = 0.51%; control frequency (f control) = 0.02%; odds ratio (OR) = 23.11) and newly identified p.Lys155Gln encoded in the C3 gene (f case = 1.06%; f control = 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. © 2013 Nature America, Inc. All rights reserved.