title: A rare nonsynonymous sequence variant in C3 is associated with high risk of age-related macular degeneration.
abstract: Through whole-genome sequencing of 2,230 Icelanders, we detected a rare nonsynonymous SNP (minor allele frequency = 0.55%) in the C3 gene encoding a p.Lys155Gln substitution in complement factor 3, which, following imputation into a set of Icelandic cases with age-related macular degeneration (AMD) and controls, associated with disease (odds ratio (OR) = 3.45; P = 1.1 × 10(-7)). This signal is independent of the previously reported common SNPs in C3 encoding p.Pro314Leu and p.Arg102Gly that associate with AMD. The association of p.Lys155Gln was replicated in AMD case-control samples of European ancestry with OR = 4.22 and P = 1.6 × 10(-10), resulting in OR = 3.65 and P = 8.8 × 10(-16) for all studies combined. In vitro studies have suggested that the p.Lys155Gln substitution reduces C3b binding to complement factor H, potentially creating resistance to inhibition by this factor. This resistance to inhibition in turn is predicted to result in enhanced complement activation.
authors.affiliation: 1] deCODE Genetics/Amgen, Reykjavik, Iceland. [2] School of Engineering and Natural Sciences, University of Iceland, Reykjavik, Iceland. [3].
authors.forename: Hannes
authors.initials: H
authors.lastname: Helgason
authors.forename: Patrick
authors.initials: P
authors.lastname: Sulem
authors.forename: Maheswara R
authors.initials: MR
authors.lastname: Duvvari
authors.forename: Hongrong
authors.initials: H
authors.lastname: Luo
authors.forename: Gudmar
authors.initials: G
authors.lastname: Thorleifsson
authors.forename: Hreinn
authors.initials: H
authors.lastname: Stefansson
authors.forename: Ingileif
authors.initials: I
authors.lastname: Jonsdottir
authors.forename: Gisli
authors.initials: G
authors.lastname: Masson
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Gudbjartsson
authors.forename: G Bragi
authors.initials: GB
authors.lastname: Walters
authors.forename: Olafur Th
authors.initials: OT
authors.lastname: Magnusson
authors.forename: Augustine
authors.initials: A
authors.lastname: Kong
authors.forename: Thorunn
authors.initials: T
authors.lastname: Rafnar
authors.forename: Lambertus A
authors.initials: LA
authors.lastname: Kiemeney
authors.forename: Frederieke E
authors.initials: FE
authors.lastname: Schoenmaker-Koller
authors.forename: Ling
authors.initials: L
authors.lastname: Zhao
authors.forename: Camiel J F
authors.initials: CJ
authors.lastname: Boon
authors.forename: Yaojun
authors.initials: Y
authors.lastname: Song
authors.forename: Sascha
authors.initials: S
authors.lastname: Fauser
authors.forename: Michelle
authors.initials: M
authors.lastname: Pei
authors.forename: Tina
authors.initials: T
authors.lastname: Ristau
authors.forename: Shirrina
authors.initials: S
authors.lastname: Patel
authors.forename: Sandra
authors.initials: S
authors.lastname: Liakopoulos
authors.forename: Johannes P H
authors.initials: JP
authors.lastname: van de Ven
authors.forename: Carel B
authors.initials: CB
authors.lastname: Hoyng
authors.forename: Henry
authors.initials: H
authors.lastname: Ferreyra
authors.forename: Yaou
authors.initials: Y
authors.lastname: Duan
authors.forename: Paul S
authors.initials: PS
authors.lastname: Bernstein
authors.forename: Asbjorg
authors.initials: A
authors.lastname: Geirsdottir
authors.forename: Gudleif
authors.initials: G
authors.lastname: Helgadottir
authors.forename: Einar
authors.initials: E
authors.lastname: Stefansson
authors.forename: Anneke I
authors.initials: AI
authors.lastname: den Hollander
authors.forename: Kang
authors.initials: K
authors.lastname: Zhang
authors.forename: Fridbert
authors.initials: F
authors.lastname: Jonasson
authors.forename: Haraldur
authors.initials: H
authors.lastname: Sigurdsson
authors.forename: Unnur
authors.initials: U
authors.lastname: Thorsteinsdottir
authors.forename: Kari
authors.initials: K
authors.lastname: Stefansson
mesh_terms: D019943:Amino Acid Substitution; D001483:Base Sequence; D003167:Complement Activation / Q000235:genetics; D003176:Complement C3 / Q000235:genetics*; D003179:Complement C3b / Q000276:immunology / Q000378:metabolism*; D017242:Complement Factor H / Q000276:immunology / Q000378:metabolism; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D007055:Iceland; D008268:Macular Degeneration / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012306:Risk; D017422:Sequence Analysis, DNA
chemical_list: C493495:CFH protein, human; D003176:Complement C3; D003179:Complement C3b; D017242:Complement Factor H
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