Role of Plasma Fatty Acid in Age-Related Macular Degeneration: Insights from a Mendelian Randomization Analysis

Background An imbalance in lipid metabolism has been linked to the development of AMD, but the causal relationship between AMD and plasma fatty acids (FAs) remains controversial. Using a two-sample Mendelian randomization (MR) approach, we sought to evaluate the impact of specific FA plasma levels on various AMD subtypes’ risk. Methods We analysed genome-wide association data of circulating FAs from 115,006 European-descended individuals in the UK Biobank. This data was used in a two-sample MR framework to assess the potential role of circulating FAs in developing wet and dry AMD. Sensitivity analyses were conducted to ensure the robustness of our findings. Additional multivariable and locus-specific MR analyses were conducted to evaluate FA’s direct effects on AMD subtypes, minimizing biases from lipoprotein-related traits and triglycerides. Results Mendelian randomization revealed associations of omega-3 was associated with decreased wet (OR 0.78, 95%CI 0.66–0.92) and dry AMD (0.85, 0.74–0.97) risk. Notably, the omega-6 to omega-3 ratio showed potential causal effects on both wet (1.27, 1.03–1.56) and dry AMD (1.18, 1.02–1.37). Multivariable MR suggested that the causal relationship of omega-3, omega-6 to omega-3 ratio on wet AMD persists after conditioning on other lipids, albeit with slightly diminished evidence strength. These results, however, did not withstand multiple testing correction and the exclusion of SNPs within the FADS locus from dry AMD samples. Conclusions The connections between plasma FA concentrations and AMD, suggest potential causal role of omega-3, and the omega-6 to omega-3 ratio in wet AMD. These results underscore the impact of imbalanced circulating omega-3 and omega-6 FA ratio on AMD pathophysiology from MR perspective.