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

Abstract

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.

Figure 1

Flowchart showing exclusion criteria for RPE-BM and retinal macular thickness association analyses involving CFI RVs. Abbreviations: CFI = complement factor I gene, RPE-BM = retinal pigment epithelium-Bruch’s membrane complex, RVs = rare variants, SD-OCT = spectral domain optical coherence tomography.

Figure 2

Significance of reduced thickness in OCT-derived metrics across the macula. Significance of multivariable testing for different genotypes and RPE-BM (above) or retinal (below) thinning in each ETDRS macular subfield using stepwise linear regression. Significant differences are indicated by ^*for P < 0.05, ^**for P < 0.01 and ^***for P < 0.001. Abbreviations: ARMS2 = age-related maculopathy susceptibility protein 2 gene, C = central macular subfield, CFH = complement factor H gene, CFI = complement Factor I gene, II = inner inferior subfield, IN = inner nasal subfield, IS = inner superior subfield, IT = inner temporal subfield, OI = outer inferior subfield, ON = outer nasal subfield, OS = outer superior subfield, OT = outer temporal subfield, RV = rare variant, VUS = variant of uncertain significance.

Figure 3

Relationship of mean macular RPE and retinal thickness with age. Scatter plots of mean RPE-BM (A–D) and retinal (E–H) thickness versus age for CFI type 1 RV (A, E), CFI VUS (B, F), CFH p.Y402H (C, G) and ARMS2/HTRA1 risk haplotype (D, H). Genotype groups are indicated by color (blue for non-carriers/WT, yellow for CFI RV carriers and p.Y402H or p.A69S heterozygotes, and dark gray for p.Y402H or p.A69S homozygotes). Each plotted point represents the mean RPE-BM or retinal macular thickness for each genotype group at each year of age. Linear model regression lines and 95% CIs (light gray bands) are also shown. Fitted coefficients, R² and P-values are indicated above each plot. Abbreviations: ARMS2 = age-related maculopathy susceptibility protein 2 gene, CFH = complement Factor H gene, CFI = complement factor I gene, RV = rare variant, VUS = variant of uncertain significance.

Figure 4

Forest plot of odds ratios for AMD diagnosis from multilevel (mixed effects) logistic regression analysis adjusted for age, gender, ethnicity, smoking status and genotype as fixed effects, and recruitment site as a random effect. Abbreviations: ARMS2 = age-related maculopathy susceptibility protein 2 gene, CFH = complement Factor H gene, CFI = complement Factor I gene, RV = rare variant, VUS = variant of uncertain significance.