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

Abstract Context 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 1 or more n-6 PUFAs account for this relationship remains unclear. Objective 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 2-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% CI 0.945 to 0.990; P = .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 = .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. Conclusion 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.