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

XW Zhan, DE Larson, CL Wang, DC Koboldt, YV Sergeev, RS Fulton, LL Fulton, CC Fronick, KE Branham, J Bragg-Gresham, G Jun, YN Hu, HM Kang, DJ Liu, M Othman, M Brooks, R Ratnapriya, A Boleda, F Grassmann, C von StrachwitzLM Olson, Gabriëlle Buitendijk, Bert Hofman, Cornelia Duijn, V Cipriani, AT Moore, H Shahid, YD Jiang, YP Conley, DJ Morgan, IK Kim, MP Johnson, S Cantsilieris, AJ Richardson, RH Guymer, HR Luo, H Ouyang, C Licht, FG Pluthero, MM Zhang, Kai Zhang, PN Baird, J Blangero, ML Klein, LA Farrer, MM DeAngelis, DE Weeks, MB Gorin, JRW Yates, Caroline Klaver, MA Pericak-Vance, JL Haines, BHF Weber, RK Wilson, JR Heckenlively, EY Chew, D Stambolian, ER Mardis, A Swaroop, GR Abecasis

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122 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 languageUndefined/Unknown
Pages (from-to)1375-+
JournalNature Genetics
Issue number11
Publication statusPublished - 2013

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