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

Xiaowei Zhan, David E. Larson, Chaolong Wang, Daniel C. Koboldt, Yuri V. Sergeev, Robert S. Fulton, Lucinda L. Fulton, Catrina C. Fronick, Kari E. Branham, Jennifer Bragg-Gresham, Goo Jun, Youna Hu, Hyun Min Kang, Dajiang Liu, Mohammad Othman, Matthew Brooks, Rinki Ratnapriya, Alexis Boleda, Felix Grassmann, Claudia Von StrachwitzLana M. Olson, Gabriëlle H.S. Buitendijk, Albert Hofman, Cornelia M. Van Duijn, Valentina Cipriani, Anthony T. Moore, Humma Shahid, Yingda Jiang, Yvette P. Conley, Denise J. Morgan, Ivana K. Kim, Matthew P. Johnson, Stuart Cantsilieris, Andrea J. Richardson, Robyn H. Guymer, Hongrong Luo, Hong Ouyang, Christoph Licht, Fred G. Pluthero, Mindy M. Zhang, Kang Zhang, Paul N. Baird, John Blangero, Michael L. Klein, Lindsay A. Farrer, Margaret M. DeAngelis, Daniel E. Weeks, Michael B. Gorin, John R.W. Yates, Caroline C.W. Klaver, Margaret A. Pericak-Vance, Jonathan L. Haines, Bernhard H.F. Weber, Richard K. Wilson, John R. Heckenlively, Emily Y. Chew, Dwight Stambolian, Elaine R. Mardis, Anand Swaroop, Goncalo R. Abecasis

Research output: Contribution to journalLetterpeer-review

134 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)1375-1381
Number of pages7
JournalNature Genetics
Issue number11
StatePublished - Nov 2013

All Science Journal Classification (ASJC) codes

  • Genetics


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