Causal associations between fatty acid measures and schizophrenia – a two-sample Mendelian randomization study

Objective Although studies suggest that erythrocyte concentrations of omega-3 and omega-6 fatty acids are lower in individuals with schizophrenia, evidence of beneficial effects of omega-3 fatty acid supplementation is limited. This study therefore aimed to determine whether omega-3 and omega-6 fatty acid levels are causally related to schizophrenia. Methods Causality was evaluated using the inverse variance weighted (IVW) 2-sample Mendelian randomization (MR) method using fatty acid levels and schizophrenia genome-wide association study results. Weighted median, weighted mode, and MR Egger regression methods were used as sensitivity analyses. To address the mechanism, analyses were performed using instruments within the FADS and ELOVL2 genes. Multivariable MR (MVMR) was used to estimate direct effects of omega-3 fatty acids on schizophrenia, independent of omega-6 fatty acids, lipoproteins and triglycerides. Results MR analyses indicated that long-chain omega-3 and omega-6 fatty acid levels were associated with lower risk of schizophrenia (docosahexaenoic acid [DHA] ORIVW: 0.83, 95% CI: 0.75-0.92). In contrast, short-chain fatty acids were associated with an increased risk of schizophrenia (alpha-linolenic acid ORIVW: 1.07, 95% CI: 0.98-1.18). Causal effects were consistent across sensitivity and FADS single-SNP analyses. MVMR indicated that the protective effect of DHA on schizophrenia persisted after conditioning on other lipids (ORIVW: 0.84, 95% CI: 0.71-1.01). Conclusions Results: are consistent with protective effects of long-chain omega-3 and omega-6 fatty acids on schizophrenia suggesting that people with schizophrenia may have difficulty converting short-chain to long-chain PUFAs. Long-chain PUFA supplementation or diet enrichment, particularly in higher risk individuals, might help prevent onset of disorder.