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*

*Corresponding author for this work

Research output: Contribution to journalLetterpeer-review

132 Citations (Scopus)


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
Pages (from-to)1375-1379
Number of pages7
JournalNature Genetics
Issue number11
Early online date15 Sept 2013
Publication statusPublished - 1 Nov 2013

Bibliographical note

We thank all study participants for their generous volunteering. We thank B. Li, W. Chen, C. Sidore, T. Teslovich, L. Fritsche and M. Boehnke for useful discussion and suggestions. This project was supported by grants from the US National Institutes of Health (National Eye Institute, National Human Genome Research Institute; grants EY022005, HG007022, HG005552, EY016862, U54HG003079 and EY09859); the Medical Research Council, UK (grant G0000067); the Deutsche Forschungsgemeinschaft (grant WE1259/19-2); the Alcon Research Institute; The UK Department of Health's National Institute for Health Research (NIHR) Biomedical Research Centre for Ophthalmology at Moorfields Eye Hospital and the UCL Institute of Ophthalmology; Research to Prevent Blindness (New York); the Thome Memorial Foundation; the Harold and Pauline Price Foundation; and the National Health and Medical Research Council of Australia (NHMRC) Clinical Research Excellence (grant 529923, NHMRC practitioner fellowship 529905 and NHMRC Senior Research Fellowship 1028444). The study was also supported by the Intramural Research Program (Computational Medicine Initiative) of the National Eye Institute. The Centre for Eye Research Australia (CERA) receives operational infrastructure support from the Victorian Government. The views expressed in the publication are those of the authors and not necessarily those of their employers or the funders.


  • Diseaes
  • Genetic association study
  • Medical genetics
  • Sequencing


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