A rare penetrant mutation in CFH confers high risk of age-related macular degeneration
Open accessAbstract
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.
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Patients with genetic abnormalities in the complement system tend to only develop overt disease in one organ (such as AMD, C3 glomerulopathy, or atypical haemolytic uraemic syndrome), even in the presence of rare, pathogenic variants or haploinsufficiency of FH and FI.
“patients with genetic abnormalities in the complement system tend to only develop overt disease in one organ (such as AMD, C3 glomerulopathy, or atypical haemolytic uraemic syndrome), even in the presence of rare, pathogenic variants or haploinsufficiency of FH and FI [81,220,221,222,223].”
From Bruch’s Membrane: A Key Consideration with Complement-Based Therapies for Age-Related Macular Degeneration (2023) · cites this paper as [222]
Although a common deletion of CFHR1 and CFHR3 has been proposed, there was only modest signal in this study, likely due to linkage disequilibrium with the most significantly associated variants in the locus (r2=.31 between rs10737680 and 1000 Genomes Project MERGED_DEL_2_6731).
“Although a common deletion of the CFHR1 and CFHR3 genes has been proposed42,43, there was only modest signal in this study which is likely due to linkage disequilibrium with our most significantly associated variants in the locus (r2=.31 between rs10737680 and 1000 Genomes Project MERGED_DEL_2_6731) as previously suggested34.”
From Seven new loci associated with age-related macular degeneration (2013) · cites this paper as [34]
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- Authors
- Raychaudhuri, S., Iartchouk, O., Chin, K., Tan, P. L., Tai, A. K., Ripke, S., Gowrisankar, S., Vemuri, S., Montgomery, K., Yu, Y., Reynolds, R., Zack, D. J., Campochiaro, B., Campochiaro, P., Katsanis, N., Daly, M. J., & Seddon, J. M.
- Affiliations
- Brigham and Women's Hospital (US)
- Tufts Medical Center (US)
- Duke University (US)
- Tufts University (US)
- Broad Institute (US)
- Johns Hopkins University (US)
- Corresponding author
- Raychaudhuri, Soumya
- Seddon, Johanna M
- ORCID
- Venue
- Nature Genetics
- Published
- 2011-10-23
- Volume
- 43
- Issue
- 12
- Pages
- 1232-1236
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- PMC
- PMC3225644
- OpenAlex
- W2097013149
- Cited by
- 323
- References
- 47
- Citations by year
- 2026: 9 · 2025: 11 · 2024: 11 · 2023: 10 · 2022: 15 · 2021: 23 · 2020: 18 · 2019: 17 · 2018: 18 · 2017: 21 · 2016: 38 · 2015: 30 · 2014: 41 · 2013: 35 · 2012: 24
- FWCI
- 30.60
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Research Explorer (The University of Manchester) (submittedVersion)
- Funders
- National Heart, Lung, and Blood Institute (R01HL087676)
- National Institute of Mental Health (U01MH085520)
- National Eye Institute (R01 EY 11309, R01EY011309)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (K08AR055688)
- Topics
- Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
- Life Sciences › Immunology and Microbiology › Immunology › Complement system in diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Keywords
- age-related macular degeneration, complement factor H, loss-of-function alleles, haplotypes, disease susceptibility, atypical hemolytic uremic syndrome, complement system, age of onset, genetic association
- MeSH terms
- Aged, Aged, 80 and over, Female, Haplotypes, Heterozygote, Humans, Macular Degeneration, Male, Middle Aged, Risk Factors, Linkage Disequilibrium, Case-Control Studies, Complement Factor H, Sequence Analysis, DNA, Penetrance, Genetic Predisposition to Disease, Mutation, Missense, Polymorphism, Single Nucleotide, Principal Component Analysis, High-Throughput Nucleotide Sequencing
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