Evidence for Genetic Causal Relationships Between Multiple Immune-Mediated Inflammatory Diseases and Age-Related Macular Degeneration: A Univariable and Multivariable Mendelian Randomization Study

Abstract Introduction With the global aging population on the rise, age-related macular degeneration (AMD) poses a growing healthcare burden. Prior research hints at immune-mediated inflammatory diseases (IMIDs) potentially elevating AMD risk via diverse mechanisms. However, causality remains disputed as a result of confounding factors. Hence, our Mendelian randomization (MR) study aims to untangle this link, mitigating confounding effects to explore the IMID–AMD causal relationship. This study aims to investigate the causal relationship between IMIDs and AMD, providing new strategies for the prevention and treatment of AMD in clinical practice. Methods This study was registered with PROSPERO, CRD42023469815. We obtained data on IMIDs and AMD from Genome-Wide Association Studies (GWAS) summary statistics and the FinnGen consortium. Rigorous selection steps were applied to screen for eligible instrumental single nucleotide polymorphisms (SNPs). We conducted univariate Mendelian randomization, inverse variance-weighted (IVW), weighted median, Mendelian randomization-Egger (MR-Egger), and multivariate Mendelian randomization (MVMR) analyses. Various sensitivity analysis methods were employed to assess pleiotropy and heterogeneity. The aim was to explore the causal relationships between IMIDs and AMD. Results The MR analysis revealed that Crohn’s disease (CD) (IVW: odd ratios (OR) 1.05, 95% CI (confidence interval) 1.01–1.10, p = 0.007), rheumatoid arthritis (RA) (IVW: OR 1.09, 95% CI 1.04–1.15, p = 0.0001), and type 1 diabetes (T1D) (IVW: OR 1.05, 95% CI 1.02–1.09, p = 0.001) were correlated with an elevated risk of AMD, while multiple sclerosis (MS) (IVW: OR 2.78E−18, 95% CI 2.23E−31 to 3.48E−05, p = 0.008) appeared to be protective against AMD. These findings were supported by an array of MR analysis methodologies and the MVMR approach. Conclusion Our study results, based on MR, provide genetic evidence indicating a causal relationship between specific IMIDs and AMD. CD, RA, and T1D are factors increasing the risk of AMD, while MS may have a protective effect.