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

Amy V Jones; Stuart MacGregor; Xikun Han; James Francis; Claire Harris; SCOPE Study group; David Kavanagh; Andrew Lotery; Nadia Waheed

doi:10.1016/j.xops.2022.100146

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

Ophthalmol Sci. 2022 Jun;2(2):100146. doi: 10.1016/j.xops.2022.100146. Epub 2022 Mar 18.

Authors

Amy V Jones¹, Stuart MacGregor², Xikun Han^{2

3}, James Francis¹, Claire Harris^{1

4}; SCOPE Study group; David Kavanagh^{4

5}, Andrew Lotery^{6

7}, Nadia Waheed^{1

8}

Affiliations

¹ Gyroscope Therapeutics Ltd, London, UK.
² Statistical Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
³ School of Medicine, University of Queensland, Brisbane, Australia.
⁴ Clinical & Translational Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK.
⁵ National Renal Complement Therapeutics Centre, Royal Victoria Infirmary, Newcastle upon Tyne, UK.
⁶ Clinical Neurosciences, Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK.
⁷ Southampton Eye Unit, University Hospital Southampton NHS Foundation Trust, Southampton, UK.
⁸ Department of Ophthalmology, Tufts University School of Medicine, Boston MA, United States.

Abstract

Importance: 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.

Objective: Can genetic factors be used to infer whether low circulating CFI is associated with AAMD risk?

Design: Two-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.

Participants: We 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 from a 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.

Results: We 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=2.1×10^-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=1.9×10^-8). The rare variant rs141853578 explained a further 1.7% of phenotypic variance. To benchmark the effect of low CFI levels on AAMD 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=1.85×10^-8).

Conclusion and relevance: Excellent 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.

Keywords: Advanced age-related macular degeneration; CFI; Factor I; biomarkers; genetics.

Abstract

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