title: Identification of a rare coding variant in complement 3 associated with age-related macular degeneration.
abstract: 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.
authors.affiliation: 1] Department of Biostatistics, Center for Statistical Genetics, University of Michigan School of Public Health, Ann Arbor, Michigan, USA. [2].
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mesh_terms: D000375:Aging; D003176:Complement C3 / Q000235:genetics* / Q000378:metabolism; D017242:Complement Factor H / Q000378:metabolism; D003170:Complement Pathway, Alternative / Q000276:immunology*; D005787:Gene Frequency; D014644:Genetic Variation; D005838:Genotype; D008268:Macular Degeneration / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide
chemical_list: C493495:CFH protein, human; D003176:Complement C3; D017242:Complement Factor H
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