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

• Published in: Nature genetics Vol. 45; no. 11; pp. 1375 - 1379
• Main Authors: 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 K, 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
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.11.2013; Nature Publishing Group
• Subjects: 631/208/1516; 631/208/205; 631/208/514; 692/699; Aging; Agriculture; Algorithms; Animal Genetics and Genomics; Biomedicine; Cancer Research; Colleges & universities; Complement C3 - genetics; Complement C3 - metabolism; Complement Factor H - metabolism; Complement Pathway, Alternative - immunology; Gene Frequency; Gene Function; Genealogy; Genetic aspects; Genetic code; Genetic susceptibility; Genetic Variation; Genomes; Genomics; Genotype; Human Genetics; Hypotheses; Identification and classification; letter; Macular degeneration; Macular Degeneration - genetics; Polymorphism, Single Nucleotide; Proteins; Quality control; Testing
• ISSN: 1061-4036; 1546-1718; 1546-1718
• DOI: 10.1038/ng.2758

Goncalo Abecasis and colleagues report identification of a rare coding variant in the complement 3 gene that is associated with age-related macular degeneration. 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.