Association between Arachidonic Acid and the Risk of Schizophrenia: A Cross-National Study and Mendelian Randomization Analysis

Polyunsaturated fatty acids (PUFAs), especially long-chain PUFAs (LCPUFAs), are crucial for both the structural and functional integrity of cells. PUFAs have been reported to be insufficient in schizophrenia, and the resulting cell membrane impairments have been hypothesized as an etiological mechanism. However, the impact of PUFA deficiencies on the onset of schizophrenia remain uncertain. We investigated the associations between PUFAs consumption and schizophrenia incidence rates through correlational analyses and conducted Mendelian randomization analyses to reveal the causal effects. Using dietary PUFA consumption and national schizophrenia incidence rates in 24 countries, we found that incidence rates of schizophrenia were inversely correlated with arachidonic acid (AA) and ω-6 LCPUFA consumption (r(AA) = −0.577, p < 0.01; r(ω-6 LCPUFA) = −0.626, p < 0.001). Moreover, Mendelian randomization analyses revealed that genetically predicted AA and gamma-linolenic acid (GLA) were protective factors against schizophrenia (OR(AA) = 0.986, OR(GLA) = 0.148). In addition, no significant relationships were observed between schizophrenia and docosahexaenoic acid (DHA) or other ω-3 PUFAs. These findings show that the deficiencies of ω-6 LCPUFAs, especially AA, are associated with schizophrenia risk, which sheds novel insight into the etiology of schizophrenia and a promising diet supplementation for the prevention and treatment of schizophrenia.