Leukocytes and age-related macular degeneration.

Age-related macular degeneration (AMD) is a leading cause of vision loss. Leukocyte subtypes have been implicated in the pathogenesis, but causality remains uncertain. We investigated whether leukocyte counts are causally associated with clinically diagnosed AMD using observational and genetic analyses in three prospective cohorts. We included 117,714 individuals from the Copenhagen General Population Study (CGPS), 388,758 from the UK Biobank (UKB), and 285,612 from the Million Veteran Program (MVP), all of European ancestry and without clinically diagnosed AMD at baseline. In total, 27,130 incident AMD cases were identified. Baseline leukocyte counts were log2-transformed and standardized. Observational associations with incident AMD were estimated using Cox regression in CGPS and UKB, and then meta-analysed. Genetic instruments derived from genome-wide association studies were used for one-sample mendelian randomization (MR) and multivariable MR (MVMR) analyses in UKB and MVP, and estimates then meta-analysed. Observationally, a 1-standard deviation (SD) increase in leukocyte (Hazard ratio (HR) [95% confidence interval (CI)], 1.07 [1.05-1.09]), neutrophil (1.07 [1.05-1.09]), monocyte (1.05 [1.03-1.07]), basophil (1.06 [1.04-1.08]), and eosinophil (1.05 [1.03-1.06]) counts was associated with increased risk of clinically diagnosed AMD (all p < 0.0001). In the genetic analyses, a 1-SD increase in genetically determined eosinophil counts was causally associated with increased risk of clinically diagnosed AMD in the MR (OR [95% CI], 1.07 [1.00-1.15]; p = 0.038) and MVMR (OR [95% CI], 1.12 [1.03-1.21]; p = 0.006) analyses. This large-scale study provides observational and genetic evidence that elevated eosinophil counts are causally linked to risk of clinically diagnosed AMD. These findings highlight systemic eosinophil-driven immune pathways as potential contributors to AMD pathogenesis.