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A rare penetrant mutation in CFH confers high risk of age-related macular degeneration.
- Source :
-
Nature genetics [Nat Genet] 2011 Oct 23; Vol. 43 (12), pp. 1232-6. Date of Electronic Publication: 2011 Oct 23. - Publication Year :
- 2011
-
Abstract
- Two common variants in the gene encoding complement factor H (CFH), the Y402H substitution (rs1061170, c.1204C>T)(1-4) and the intronic rs1410996 SNP(5,6), explain 17% of age-related macular degeneration (AMD) liability. However, proof for the involvement of CFH, as opposed to a neighboring transcript, and knowledge of the potential mechanism of susceptibility alleles are lacking. Assuming that rare functional variants might provide mechanistic insights, we used genotype data and high-throughput sequencing to discover a rare, high-risk CFH haplotype with a c.3628C>T mutation that resulted in an R1210C substitution. This allele has been implicated previously in atypical hemolytic uremic syndrome, and it abrogates C-terminal ligand binding(7,8). Genotyping R1210C in 2,423 AMD cases and 1,122 controls demonstrated high penetrance (present in 40 cases versus 1 control, P = 7.0 × 10(-6)) and an association with a 6-year-earlier onset of disease (P = 2.3 × 10(-6)). This result suggests that loss-of-function alleles at CFH are likely to drive AMD risk. This finding represents one of the first instances in which a common complex disease variant has led to the discovery of a rare penetrant mutation.
- Subjects :
- Aged
Aged, 80 and over
Case-Control Studies
Complement Factor H genetics
Female
Haplotypes
Heterozygote
High-Throughput Nucleotide Sequencing
Humans
Linkage Disequilibrium
Macular Degeneration pathology
Male
Middle Aged
Mutation, Missense
Polymorphism, Single Nucleotide
Principal Component Analysis
Risk Factors
Sequence Analysis, DNA
Genetic Predisposition to Disease
Macular Degeneration genetics
Penetrance
Subjects
Details
- Language :
- English
- ISSN :
- 1546-1718
- Volume :
- 43
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- Nature genetics
- Publication Type :
- Academic Journal
- Accession number :
- 22019782
- Full Text :
- https://doi.org/10.1038/ng.976