title: Rare variants in CFI, C3 and C9 are associated with high risk of advanced age-related macular degeneration.
abstract: To define the role of rare variants in advanced age-related macular degeneration (AMD) risk, we sequenced the exons of 681 genes within all reported AMD loci and related pathways in 2,493 cases and controls. We first tested each gene for increased or decreased burden of rare variants in cases compared to controls. We found that 7.8% of AMD cases compared to 2.3% of controls are carriers of rare missense CFI variants (odds ratio (OR) = 3.6; P = 2 × 10(-8)). There was a predominance of dysfunctional variants in cases compared to controls. We then tested individual variants for association with disease. We observed significant association with rare missense alleles in genes other than CFI. Genotyping in 5,115 independent samples confirmed associations with AMD of an allele in C3 encoding p.Lys155Gln (replication P = 3.5 × 10(-5), OR = 2.8; joint P = 5.2 × 10(-9), OR = 3.8) and an allele in C9 encoding p.Pro167Ser (replication P = 2.4 × 10(-5), OR = 2.2; joint P = 6.5 × 10(-7), OR = 2.2). Finally, we show that the allele of C3 encoding Gln155 results in resistance to proteolytic inactivation by CFH and CFI. These results implicate loss of C3 protein regulation and excessive alternative complement activation in AMD pathogenesis, thus informing both the direction of effect and mechanistic underpinnings of this disorder.
authors.affiliation: 1] Ophthalmic Epidemiology and Genetics Service, New England Eye Center, Tufts Medical Center, Boston, Massachusetts, USA. [2] Department of Ophthalmology, Tufts University School of Medicine, Boston, Massachusetts, USA. [3] Sackler School of Graduate Biomedical Sciences, Tufts University, Boston, Massachusetts, USA.
authors.forename: Johanna M
authors.initials: JM
authors.lastname: Seddon
authors.forename: Yi
authors.initials: Y
authors.lastname: Yu
authors.forename: Elizabeth C
authors.initials: EC
authors.lastname: Miller
authors.forename: Robyn
authors.initials: R
authors.lastname: Reynolds
authors.forename: Perciliz L
authors.initials: PL
authors.lastname: Tan
authors.forename: Sivakumar
authors.initials: S
authors.lastname: Gowrisankar
authors.forename: Jacqueline I
authors.initials: JI
authors.lastname: Goldstein
authors.forename: Michael
authors.initials: M
authors.lastname: Triebwasser
authors.forename: Holly E
authors.initials: HE
authors.lastname: Anderson
authors.forename: Jennyfer
authors.initials: J
authors.lastname: Zerbib
authors.forename: David
authors.initials: D
authors.lastname: Kavanagh
authors.forename: Eric
authors.initials: E
authors.lastname: Souied
authors.forename: Nicholas
authors.initials: N
authors.lastname: Katsanis
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Daly
authors.forename: John P
authors.initials: JP
authors.lastname: Atkinson
authors.forename: Soumya
authors.initials: S
authors.lastname: Raychaudhuri
mesh_terms: D000375:Aging; D019943:Amino Acid Substitution; D001483:Base Sequence; D003167:Complement Activation / Q000235:genetics; D003176:Complement C3 / Q000235:genetics*; D003186:Complement C9 / Q000235:genetics*; D017244:Complement Factor I / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D008268:Macular Degeneration / Q000235:genetics*; D012306:Risk; D017422:Sequence Analysis, DNA
chemical_list: D003176:Complement C3; D003186:Complement C9; C493611:CFI protein, human; D017244:Complement Factor I
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