Geographic atrophy in patients with age-related macular degeneration is associated with rare variants in complement factor H and complement factor I

Purpose: To describe the phenotype of patients with age-related macular degeneration (AMD) carrying rare genetic variants in the complement factor H (CFH) and complement factor I (CFI) genes.Design: Cross-sectional study.Participants: 234 AMD patients carrying rare variants in CFH (n=134) and CFI (n=100), and 234 AMD noncarriers.Methods: Genetic data of AMD patients from the European Genetic Database were filtered for rare coding and splice-site variants in CFH and CFI.For each carrier an age-matched ( 2 years) AMD patient without rare variants in CFH and CFI (noncarrier) was selected.Phenotypic characteristics on color fundus photographs (CFP) were graded according to the Rotterdam Classification and compared between carriers and noncarriers by univariate generalized estimating equations binary logistic regression analyses with a Bonferroni correction for multiple comparisons.We performed sub-analyses for pathogenic rare variants only, and we analyzed CFH and CFI carriers separately. Main Outcome Measures: Phenotypic characteristics on CFP.Results: Geographic atrophy (GA) and intermediate AMD, and features predominant drusen type, largest drusen size and drusen area were associated with carriership of rare pathogenic variants in CFH (P < 0.001, P = 0.002, P < 0.001 and P < 0.001, respectively).GA and intermediate AMD, and features drusen size, drusen area and pigmentation were associated with carriership of rare pathogenic variants in CFI (P = 0.01, P = 0.006, P < 0.001 and P = 0.006, respectively).Furthermore, carriers of rare pathogenic variants in CFH were younger (P < 0.001) and had a lower genetic risk score (GRS) for common AMD-associated variants compared to noncarriers (mean (SD) GRS 0.83 (1.01) vs 1.41 (1.21), P = 0.03). Conclusions:In this study, AMD patients carrying rare variants in CFH and CFI had a more severe drusen phenotype, and a higher frequency of GA at a relatively early age.Identifying this distinct phenotype could aid in pinpointing individuals who are more likely to benefit from complement inhibiting therapies.