ArticleInvestigative ophthalmology & visual science2017
Systematic Functional Testing of Rare Variants: Contributions of CFI to Age-Related Macular Degeneration.
Article in Investigative ophthalmology & visual science, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 21 citations in OpenAlex.
- Hi-C informed kernel association test for integrating 3D genome structure into variant-set analysis.Briefings in bioinformatics · 2026Article
- Disease Progression in Age-Related Macular Degeneration Patients Carrying Rare Variants in the Complement Factor H or Complement Factor I Genes.Investigative ophthalmology & visual science · 2025Article
- Hi-C informed kernel association test: integrating 3-dimensional genome structure into variant-set association for whole-genome sequencing data.bioRxiv : the preprint server for biology · 2025Article
- Pathogenic variants in TMEM184B cause a neurodevelopmental syndrome associated with alteration of metabolic signaling.American journal of human genetics · 2025Article
- Pathogenic variants inmedRxiv : the preprint server for health sciences · 2025Article
- A cross-tissue transcriptome-wide association study identified susceptibility genes for age-related macular degeneration.Scientific reports · 2025Article
- The role of complement factor I rare genetic variants in age related macular degeneration in Finland.Human molecular genetics · 2025Article
- Comprehensive functional characterization of complement factor I rare variant genotypes identified in the SCOPE geographic atrophy cohort.The Journal of biological chemistry · 2024Article
- The Relationship between Complements and Age-Related Macular Degeneration and Its Pathogenesis.Journal of ophthalmology · 2024Review
- Complement Factor I Gene Variant as a Treatable Cause of Recurrent Aseptic Neutrophilic Meningitis: A Case Report.Neurology(R) neuroimmunology & neuroinflammation · 2023Article
- Rare complement factor I variants associated with reduced macular thickness and age-related macular degeneration in the UK Biobank.Human molecular genetics · 2022Article
- Complement Factor I Variants in Complement-Mediated Renal Diseases.Frontiers in immunology · 2022Article
- A novel method for real-time analysis of the complement C3b:FH:FI complex reveals dominant negativeFrontiers in immunology · 2022Article
- Patients with MPNs and retinal drusen show signs of complement system dysregulation and a high degree of chronic low-grade inflammation.EClinicalMedicine · 2022Article
- Efficient and flexible Integration of variant characteristics in rare variant association studies using integrated nested Laplace approximation.PLoS computational biology · 2021Article
- Prospective Application of Activity-Based Proteomic Profiling in Vision Research-Potential Unique Insights into Ocular Protease Biology and Pathology.International journal of molecular sciences · 2019Review
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Authors and funding
8 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Purpose: Genome-wide association (GWAS) and sequencing studies for AMD have highlighted the importance of coding variants at loci that encode components of the complement pathway. However, assessing the contribution of such alleles to AMD, especially when they are rare, remains coarse, in part because of the persistent challenge in establishing their functional relevance. Others and we have shown previously that rare alleles in complement factor I (CFI) can be tested functionally using a surrogate in vivo assay of retinal vascularization in zebrafish embryos. Here, we have implemented and scaled these tools to assess the overall contribution of rare alleles in CFI to AMD. Methods: We performed targeted sequencing of CFI in 731 AMD patients, followed by replication in a second patient cohort of 511 older healthy individuals. Systematic functional testing of all alleles and post-hoc statistical analysis of functional variants was also performed. Results: We discovered 20 rare coding nonsynonymous variants, including the previously reported G119R allele. In vivo testing led to the identification of nine variants that alter CFI; six of which are associated with hypoactive complement factor I (FI). Post-hoc analysis in ethnically matched, population controls showed six of these to be present exclusively in cases. Conclusions: Taken together, our data argue that multiple rare and ultra-rare alleles in CFI contribute to AMD pathogenesis; they improve the precision of the assessment of the contribution of CFI to AMD; and they offer a rational route to establishing both causality and direction of allele effect for genes associated with this disorder.
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