Evaluating a Causal Relationship between Complement Factor I Protein Level and Advanced Age-Related Macular Degeneration Using Mendelian Randomization

PURPOSE: Risk of advanced age-related macular degeneration (AAMD) is associated with rare genetic variants in the gene encoding complement factor I (CFI), which is associated with lower circulating CFI protein levels, but the nature of the relationship is unclear. Can genetic factors be used to infer whether low circulating CFI is associated with AAMD risk? DESIGN: Two-sample inverse variance-weighted Mendelian randomization (MR) was used to evaluate evidence for a relationship between CFI levels and AAMD risk, comparing CFI levels from genetically predefined subsets in AAMD and control cohorts. PARTICIPANTS: We derived genetic instruments for systemic CFI level in 3301 healthy INTERVAL study participants. To evaluate a genetic causal odds ratio (OR) for the effect of CFI levels on AAMD risk, results from an AAMD genome-wide association study from the International AMD Genomics Consortium, were combined with CFI levels from SCOPE and SIGHT AAMD patients. METHODS: Published genetic and proteomic data was combined with data from cohorts of patients with geographic atrophy (GA) in a series of MR analyses. MAIN OUTCOME MEASURES: Establishing a causal relationship for CFI on AAMD. RESULTS: One common CFI variant, rs7439493, was associated strongly with low CFI level, explaining 4.8% of phenotypic variance. Using rs7439493, MR estimates for AAMD odds increased per standard deviation (SD) CFI decrease in were 1.47 (95% confidence interval [CI], 1.30–1.65; P = 2.1 × 10(–10)). MR using rare variant (rs141853578 encoding p.Gly119Arg) indicated 1-SD decrease in CFI led to increased AAMD OR of 1.79 (95% CI, 1.46–2.19; P = 1.9 × 10(–8)). The rare variant rs141853578 explained a further 1.7% of phenotypic variance. To benchmark the effect of low CFI levels on AAMD ORs using a CFI-specific proteomic assay, we estimated the effect using CFI levels from 24 rs141853578 positive GA patients; each 1-SD reduction (3.5 μg/mL) in CFI associated with a 1.67-fold increased odds of AAMD (95% CI, 1.40–2.00; P = 1.85 × 10(–8)). CONCLUSIONS: Concordance in MR calculations provide good genetic evidence for a potentially causal role of lower CFI level increasing AAMD risk.