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

Hannah J Jones, Maria C Borges, Rebecca E Carnegie, David Mongan, Peter J Rogers, Sarah J Lewis, Andrew Thompson, Stanley Zammit

Research output: Contribution to journalArticle (Academic Journal)peer-review

Abstract

Background: Although studies suggest that concentrations of omega-3 and omega-6 fatty acids are lower in individuals with schizophrenia, evidence of beneficial effects of 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: Exposure-outcome relationships were evaluated using the inverse variance weighted (IVW) two-sample Mendelian randomization (MR) method using fatty acid levels and schizophrenia genome-wide association study (GWAS) results. GWAS results were available for European (fatty acids) and European and Asian (schizophrenia) ancestry samples. Weighted median, weighted mode, and MR Egger regression methods were used as sensitivity analyses. To address underlying mechanisms, further 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.

Findings: 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, there was weak evidence that short-chain fatty acids were associated with an increased risk of schizophrenia (alpha-linolenic acid ORIVW: 1.07, 95% CI: 0.98-1.18). 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, though evidence was slightly weaker (ORIVW: 0.84, 95% CI: 0.71-1.01).

Interpretation: 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. Further studies are required to determine whether long-chain PUFA supplementation or diet enrichment might help prevent onset of disorder.
Original languageEnglish
JournalThe Lancet Psychiatry
Publication statusAccepted/In press - 23 Jul 2021

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