Identification of a Rare Coding Variant in Complement 3 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 cont...

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Detalles Bibliográficos
Autores principales: 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.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2013
Materias:
Article
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3812337/
https://www.ncbi.nlm.nih.gov/pubmed/24036949
http://dx.doi.org/10.1038/ng.2758
Descripción
Sumario: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 (f(case) = 0.51%, f(control) = 0.02%, OR = 23.11), and newly identified K155Q in the C3 gene (f(case) = 1.06%, f(control) = 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.

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