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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  &lt; 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  &lt; 0.001 heterozygous; 95% CI −0.62 to −0.42 μm,  P  &lt; 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.

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