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Rare complement factor I variants associated with reduced macular thickness and age-related macular degeneration in the UK Biobank

Lookup NU author(s): Nik Tzoumas, Professor David KavanaghORCiD, Professor Heather Cordell, Professor David SteelORCiD



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


To evaluate potential diagnostic and therapeutic biomarkers for age-related macular degeneration (AMD), we identified 8433 UK Biobank participants with rare complement Factor I gene (CFI) variants, 579 with optical coherence tomography-derived macular thickness data. We stratified these variants by predicted gene expression and measured their association with retinal pigment epithelium-Bruch’s membrane (RPE-BM) complex and retinal thicknesses at nine macular subfields, as well as AMD risk, using multivariable regression models adjusted for the common complement Factor H gene (CFH) p.Y402H and age-related maculopathy susceptibility protein 2 gene (ARMS2) p.A69S risk genotypes. CFI variants associated with low Factor I levels predicted a thinner mean RPE-BM (95% confidence interval [CI] −1.66 to −0.37 μm, P = 0.002) and retina (95% CI −5.88 to −0.13 μm, P = 0.04) and a higher AMD risk (odds ratio [OR] = 2.26, 95% CI 1.56 to 3.27, P < 0.001). CFI variants associated with normal Factor I levels did not impact mean RPE-BM/retinal thickness (P = 0.28; P = 0.99) or AMD risk (P = 0.97). CFH p.Y402H was associated with a thinner RPE-BM (95% CI −0.31 to −0.18 μm, P < 0.001 heterozygous; 95% CI −0.62 to −0.42 μm, P < 0.001 homozygous) and retina (95% CI −0.73 to −0.12 μm, P = 0.007 heterozygous; 95% CI −1.08 to −0.21 μm, P = 0.004 homozygous). ARMS2 p.A69S did not influence RPE-BM (P = 0.80 heterozygous; P = 0.12 homozygous) or retinal thickness (P = 0.75 heterozygous; P = 0.07 homozygous). p.Y402H and p.A69S exhibited a significant allele–dose response with AMD risk. Thus, CFI rare variants associated with low Factor I levels are robust predictors of reduced macular thickness and AMD. The observed association between macular thickness and CFH p.Y402H, but not ARMS2 p.A69S, highlights the importance of complement dysregulation in early pathogenesis.

Publication metadata

Author(s): Nikolaos N, Kavanagh D, Cordell HJ, Lotery AJ, Patel PJ, Steel DH

Publication type: Article

Publication status: Published

Journal: Human Molecular Genetics

Year: 2022

Volume: 31

Issue: 16

Pages: 2678-2692

Print publication date: 15/08/2022

Online publication date: 14/03/2022

Acceptance date: 08/03/2022

Date deposited: 29/05/2022

ISSN (print): 0964-6906

ISSN (electronic): 1460-2083

Publisher: Oxford University Press


DOI: 10.1093/hmg/ddac060

PubMed id: 35285476


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