BACKGROUND: Observational studies have demonstrated a close association between polyunsaturated fatty acids (PUFAs) and acne. However, the findings of clinical trials have been inconsistent, leaving the causal relationship between PUFAs and acne unclear. OBJECTIVES: To investigate the causal association between genetically proxied PUFAs and acne risk. METHODS: Mendelian randomization (MR) was performed using single-nucleotide polymorphisms associated with PUFAs as instrumental variables. The causal associations between PUFAs and acne were estimated among 115,006 UK biobank participants and 363,927 participants of Finnish descent. RESULTS: Genetically predicted docosahexaenoic acid (DHA) levels (Beta= -0.303
95% CI: -0.480 to -0.126
p = 7.74E-04) and its percentage to total fatty acids (Beta= -0.402
95% CI: -0.651 to -0.258
p = 5.91E-06) showed a significant causal association with a decreased risk of acne. Conversely, genetically predicted percentages of linoleic acid (LA) in total fatty acids (Beta=0.768
95% CI: 0.411-0.126
p = 2.87E-04) and omega-6: omega-3 (Beta=0.373
95% CI: 0.142-0.604
p = 4.48E-03) were robustly associated with an increased risk of acne. These effects were attenuated after excluding a genetic variant of rs174528 located upstream of fatty acid desaturase 1 (FADS1), highlighting the biological link between FADS1 and delta-5 desaturase activity. Multivariable MR analysis indicated that PUFAs were causally associated with acne, independent of body mass index. CONCLUSIONS: Our study indicates that high DHA levels and their ratios to total fatty acids have causal protective effects against acne, while high LA levels and omega-6: omega-3 ratio are associated with increased acne risk. This association was largely attributable to the influence of genetic variants related to FADS1.