Genetically elevated eosinophil counts linked to AMD in European cohorts

A combined observational and genetic analysis found that higher blood eosinophil counts were associated with an increased risk of developing clinically diagnosed age-related macular degeneration, or AMD. The study included 792,084 people of European ancestry from three prospective cohorts: 117,714 in the Copenhagen General Population Study, 388,758 in the UK Biobank and 285,612 in the Million Veteran Program. None had been clinically diagnosed with AMD at baseline, and the cohorts yielded 27,130 incident cases during follow-up.

Researchers measured baseline leukocyte counts in the Copenhagen General Population Study and UK Biobank, then used Cox regression to estimate their associations with subsequently diagnosed AMD. The results from the two cohorts were meta-analyzed. The investigators also used genetic instruments derived from genome-wide association studies to conduct one-sample Mendelian randomization and multivariable Mendelian randomization in the UK Biobank and Million Veteran Program.

These genetic analyses were designed to assess whether inherited variations associated with leukocyte counts supported a causal relationship with AMD rather than merely reproducing the observational association. Observationally, a one-standard-deviation increase in the total leukocyte count was associated with a 7% higher hazard of clinically diagnosed AMD, with a hazard ratio of 1.07 and a 95% confidence interval of 1.05 to 1.09. Neutrophil counts showed the same estimated increase: a hazard ratio of 1.07, also with a 95% confidence interval of 1.05 to 1.09.

A one-standard-deviation increase in monocyte, basophil and eosinophil counts was associated with hazard ratios of 1.05, 1.06 and 1.05, respectively, with respective 95% confidence intervals of 1.03 to 1.07, 1.04 to 1.08 and 1.03 to 1.06. All five observational associations had p-values below 0.0001. The genetic evidence pointed most specifically to eosinophil counts.

In the one-sample Mendelian randomization analysis, a one-standard-deviation increase in genetically determined eosinophil count was causally associated with a 7% increase in the odds of clinically diagnosed AMD. The estimated odds ratio was 1.07, with a 95% confidence interval of 1.00 to 1.15 and p = 0.038. Multivariable Mendelian randomization produced an odds ratio of 1.12, with a 95% confidence interval of 1.03 to 1.21 and p = 0.006.

Estimates from the genetic analyses were then meta-analyzed, leading the authors to conclude that elevated eosinophil counts are causally linked to the risk of clinically diagnosed AMD and that systemic eosinophil-driven immune pathways may contribute to AMD pathogenesis. The study’s findings apply to the European-ancestry populations included in the three cohorts, and the reported endpoint was clinically diagnosed AMD. The results therefore do not quantify the risk faced by an individual with a particular eosinophil count, nor do they show that every person with elevated eosinophils will develop AMD.

The central distinction is between the prospective observations and the genetic evidence: higher counts of several leukocyte subtypes were associated with subsequent AMD diagnoses, while the Mendelian randomization analyses specifically supported a causal association for genetically elevated eosinophil counts.

Subject of Research: Leukocyte counts and incident age-related macular degeneration in three prospective European-ancestry cohorts.

Article Title: Leukocytes and age-related macular degeneration

Article References: Sandau, N., Gorman, B. R., Luo, J., Peachey, N. S., Nordestgaard, B. G., Tybjaerg-Hansen, A., Thomassen, J. Q., Iyengar, S. K., & Frikke-Schmidt, R. (2026). Leukocytes and age-related macular degeneration. European Journal of Epidemiology. https://doi.org/10.1007/s10654-026-01471-6

Image Credits: AI Generated

DOI: 10.1007/s10654-026-01471-6

Keywords: age-related macular degeneration, eosinophils, leukocytes, Mendelian randomization, prospective cohorts, immune pathways, vision loss, UK Biobank, Copenhagen General Population Study, Million Veteran Program, age-related, macular