In recent years, researchers have examined the use of polyunsaturated fatty acids (PUFA) or a low omega-6/3 ratio to protect the knee joint. The current study is based on genome-wide association study (GWAS) analysis and uses the Mendelian randomization (MR) method to evaluate the effect of total PUFA, omega-3, omega-6, and omega-6/3 ratios on osteoarthritis (OA). First, we downloaded the latest PUFA and OA GWAS data. The PUFA data were divided into four groups: total PUFA, omega-3, omega-6, and omega-6/3 ratios. The OA data were split into nine groups: hip OA (total, males, and females), knee OA (total, males, and females), and hand OA (total, males, and females). Then, qualified SNPs were selected as instrumental variables. Inverse variance weighting (IVW), weighted median, and the MR‒Egger method were used for MR analysis. Finally, MR‒Egger, MR-Presso, and Cochran's Q statistical methods were used to evaluate the heterogeneity and pleiotropy. Thirty-six IVW results showed that total PUFA, omega-3, omega-6, and omega-6/3 ratios did not significantly increase or decrease the risk of knee, hip, and hand OA. The IVW results of the effect of PUFA on OA (male and female) were as follows: total PUFA-knee OA (OR: 0.97, 95% CI: 0.92-1.02, P = 0.283)
total PUFA-hip OA (OR: 1.01, 95% CI: 0.93-1.08, P = 0.806)
total PUFA-hand OA (OR: 0.99, 95% CI: 0.91-1.07, P = 0.896). There was no obvious horizontal polytropy in all the analyses, and there was heterogeneity in some analyses. Our study does not indicate that total PUFA, mega-3, and low omega-6/3 ratios are helpful for people with OA, nor does it indicate that omega-6 increases the risk of OA. The dietary management of PUFA in OA patients needs to be performed cautiously.