Authors:
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 Strachwitz, Lana 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
Summary:
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.
Source:
Nature Genetics; (09/15/13)