Causal Effects of N-6 Polyunsaturated Fatty Acids on Age-related Macular Degeneration: A Mendelian Randomization Study

Purpose Although the role of n-6 polyunsaturated fatty acids (PUFAs) in age-related macular degeneration (AMD) has been studied in previous observational studies, the precise manner in which one or more n-6 PUFAs account for this relationship remains unclear. Using genetic instruments for n-6 PUFAs traits implemented through mendelian randomization (MR), we aimed to study possible causal associations between n-6 PUFAs and AMD. Methods The two-sample MR method was used to obtain unconfounded causal estimates. We selected genetic variants strongly associated (P < 5×10 -8) with circulating linoleic acid (LA) and arachidonic acid (AA) from a study involving 8,631 individuals and applied to an AMD case-control study (33,526 participants and 16,144 cases). The weighted median and MR Egger methods were used for the sensitivity analysis. Results Our MR analysis suggested that circulating LA was a causal protective factor for AMD, with an odds ratio (OR) estimate of 0.967 (95% confidence interval [CI] 0.945 to 0.990; P = 0.005) per percentage in total fatty acid increase in LA. In contrast, higher genetically predicted circulating AA causally increased the AMD risk (OR = 1.034; 95% CI 1.012 to 1.056; P = 0.002). Sensitivity analysis provided no indication of unknown pleiotropy. The findings from different single-nucleotide polymorphism selections and analytic methods were consistent, suggesting the robustness of the causal associations. Main conclusions Our study provided genetic evidence that circulating LA accounted for protective effects of n-6 PUFAs against the risk of AMD, whereas AA was responsible for deleterious effects on higher AMD risk.