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Evaluating a causal relationship between Complement Factor I protein level and advanced age-related macular degeneration using Mendelian Randomisation

Lookup NU author(s): Professor Claire Harris, Professor David KavanaghORCiD



This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND).


ImportanceRisk 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. ObjectiveTo determine whether genetic factors can be used to infer whether low circulating CFI is associated with the development of AAMD. DesignTwo-sample inverse variance weighted Mendelian Randomisation (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. Setting Published genetic and proteomic data was combined with data from cohorts of Geographic Atrophy (GA) patients in a series of MR analyses.ParticipantsWe derived genetic instruments for systemic CFI level in 3,301 healthy European participants in the INTERVAL study. To evaluate a genetic causal odds ratio (OR) for the effect of CFI levels on AAMD risk, we used results froma genome-wide association study of 12,711 AAMD cases and 14,590 European controls from the International AMD Genomics Consortium (IAMDGC), and CFI levels from patients entered into the research studies SCOPE and SIGHT. ResultsWe identified one common CFI variant rs7439493 which was strongly associated with low CFI level, explaining 4.8% of phenotypic variance. Using rs7439493 our MR analysis estimated that AAMD odds increased per standard deviation (SD) decrease in CFI level; OR 1.47 (95% confidence interval (CI) 1.30-1.65, P=2.1x10-10). We identified one rare variant (rs141853578 encoding p.Gly119Arg) which was genome-wide significantly associated with CFI levels after imputation; based on this, a 1 SD decrease in CFI leads to increased AAMD odds of 1.79 (95% CI 1.46-2.19, P=1.9x10-8). The rare variant rs141853578 explained a further 1.7% of phenotypic variance. To benchmark the effect of low CFI levels on AAMD odds using a CFI-specific proteomic assay, we estimated the effect using CFI levels from 24 rs141853578 positive GA patients; each 1 SD (3.5µg/mL) reduction in CFI was associated with 1.67 fold increased odds of AAMD (95% CI 1.40-2.00, P=1.85x10-8). Conclusion and relevanceExcellent concordance in direction and effect size derived from rare and common variant calculations provide good genetic evidence for a potentially causal role of lower CFI level increasing AAMD risk.

Publication metadata

Author(s): Jones AV, MacGregor S, Han X, Francis J, Harris C, Kavanagh D, Lotery A, Waheed N

Publication type: Article

Publication status: Published

Journal: Ophthalmology Science

Year: 2022

Volume: 2

Issue: 2

Online publication date: 18/03/2022

Acceptance date: 14/03/2022

Date deposited: 16/06/2023

ISSN (electronic): 2666-9145

Publisher: Elsevier


DOI: 10.1016/j.xops.2022.100146


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