Toggle Main Menu Toggle Search

Open Access padlockePrints

Rare variants in CFI, C3 and C9 are associated with high risk of advancedage-related macular degeneration.

Lookup NU author(s): Dr Holly Anderson, Professor David KavanaghORCiD


Full text for this publication is not currently held within this repository. Alternative links are provided below where available.


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 forincreased 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 raremissense CFI variants (odds ratio (OR) = 3.6; P = 2 × 10(-8)). There was apredominance of dysfunctional variants in cases compared to controls. We thentested individual variants for association with disease. We observed significant association with rare missense alleles in genes other than CFI. Genotyping in5,115 independent samples confirmed associations with AMD of an allele in C3encoding 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 theallele of C3 encoding Gln155 results in resistance to proteolytic inactivation byCFH and CFI. These results implicate loss of C3 protein regulation and excessive alternative complement activation in AMD pathogenesis, thus informing both thedirection of effect and mechanistic underpinnings of this disorder

Publication metadata

Author(s): Seddon JM, Yu Y, Miller EC, Reynolds R, Tan PL, Gowrisankar S, Goldstein JI, Triebwasser M, Anderson HE, Zerbib J, Kavanagh D, Souied E, Katsanis N, Daly MJ, Atkinson JP, Raychaudhuri S

Publication type: Article

Publication status: Published

Journal: Nature Genetics

Year: 2013

Volume: 45

Pages: 1366-1370

Print publication date: 15/09/2013

ISSN (print): 1061-4036

ISSN (electronic): 1546-1718

Publisher: Nature Publishing Group


DOI: 10.1038/ng.2741

PubMed id: 24036952


Altmetrics provided by Altmetric


Funder referenceFunder name
Edward N. & Della L. Thome Memorial Foundation
Foundation Fighting Blindness
Doris Duke Foundation
Macular Vision Research Foundation
Massachusetts Lions Eye Research Fund, Inc.
New England Eye Center, Department of Ophthalmology, Tufts University School of Medicine
F30HL103072US National Institutes of Health (NIH)
K08AR055688US National Institutes of Health (NIH)
R01-EY11309US National Institutes of Health (NIH)
U01HG0070033US National Institutes of Health (NIH)