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Geographic Atrophy in Patients with Age-Related Macular Degeneration Is Associated with Rare Variants in Complement
Anita de Breuk1, Sarah de Jong1, Bjorn Bakker1
1Department of Ophthalmology, Radboud University Medical Center, Nijmegen, The Netherlands.
Ophthalmology Science
|June 1, 2026
Summary
Rare variants in complement factor H (CFH) and complement factor I (CFI) genes are linked to a more severe age-related macular degeneration (AMD) phenotype, including geographic atrophy at an earlier age.
Area of Science:
- Ophthalmology
- Genetics
- Complement System
Background:
- Age-related macular degeneration (AMD) is a leading cause of vision loss.
- Genetic factors, particularly in the complement pathway, play a significant role in AMD pathogenesis.
- Rare variants in complement factor H (CFH) and complement factor I (CFI) genes are implicated in AMD, but their specific phenotypic associations require detailed description.
Purpose of the Study:
- To characterize the clinical phenotype of patients with age-related macular degeneration (AMD) who carry rare genetic variants in the complement factor H (CFH) and complement factor I (CFI) genes.
- To compare the phenotypic features of AMD carriers of rare CFH/CFI variants with non-carriers.
Main Methods:
- A cross-sectional study involving 234 AMD patients with rare CFH variants and 234 AMD patients with rare CFI variants, compared against 234 AMD non-carriers.
- Genetic data from the European Genetic Database were filtered for rare coding and splice-site variants in CFH and CFI.
- Phenotypic characteristics were assessed from color fundus photographs using the Rotterdam Classification and analyzed using generalized estimating equations with logistic regression, with Bonferroni correction.
Main Results:
- Carriers of rare pathogenic CFH variants showed associations with geographic atrophy, intermediate AMD, drusen type, drusen size, and drusen area.
- Carriers of rare pathogenic CFI variants were associated with geographic atrophy, intermediate AMD, drusen size, drusen area, and pigmentation.
- CFH variant carriers were younger and had a lower genetic risk score for common AMD variants compared to non-carriers.
Conclusions:
- Patients with AMD carrying rare variants in CFH and CFI exhibit a distinct, more severe drusen phenotype and a higher frequency of geographic atrophy at an earlier age.
- Identifying this specific phenotype can help in selecting individuals likely to benefit from complement-inhibiting therapies.
- These findings highlight the critical role of rare variants in CFH and CFI in AMD progression and suggest potential therapeutic targets.
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