(2013) Zhan, Xiaowei; Larson, David E.; Wang, Chaolong; Koboldt, Daniel C.; Sergeev, Yuri V.; Fulton, Robert S.; Fulton, Lucinda L.; Fronick, Catrina C.; Branham, Kari E.; Bragg-Gresham, Jennifer; Jun, Goo; Hu, Youna; Kang, Hyun Min; Liu, Dajiang; Othman, Mohammad; Brooks, Matthew; Ratnapriya, Rinki; Boleda, Alexis; Grassmann, Felix; von Strachwitz, Claudia; Olson, Lana M.; Buitendijk, Gabriëlle H.S.; Hofman, Albert; van Duijn, Cornelia M.; Cipriani, Valentina; Moore, Anthony T.; Shahid, Humma; Jiang, Yingda; Conley, Yvette P.; Morgan, Denise J.; Kim, Ivana; Johnson, Matthew P.; Cantsilieris, Stuart; Richardson, Andrea J.; Guymer, Robyn H.; Luo, Hongrong; Ouyang, Hong; Licht, Christoph; Pluthero, Fred G.; Zhang, Mindy M.; Zhang, Kang; Baird, Paul N.; Blangero, John; Klein, Michael L.; Farrer, Lindsay A.; DeAngelis, Margaret M.; Weeks, Daniel E.; Gorin, Michael B.; Yates, John R.W.; Klaver, Caroline C.W.; Pericak-Vance, Margaret A.; Haines, Jonathan L.; Weber, Bernhard H.F.; Wilson, Richard K.; Heckenlively, John R.; Chew, Emily Y.; Stambolian, Dwight; Mardis, Elaine R.; Swaroop, Anand; Abecasis, Goncalo R.
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 revealed two large-effect rare variants; previously described R1210C in the CFH gene (fcase = 0.51%, fcontrol = 0.02%, OR = 23.11), and newly identified K155Q in the C3 gene (fcase = 1.06%, fcontrol = 0.39%, OR = 2.68). The variants suggest decreased inhibition of C3 by Factor H, resulting in increased activation of the alternative complement pathway, as a key component of disease biology.
