Associations between plasma fatty acid concentrations and schizophrenia: a two-sample Mendelian randomisation study

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

*Corresponding author for this work

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

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Abstract

Summary
Background Although studies suggest that concentrations of omega-3 and omega-6 fatty acids are lower in individuals with schizophrenia, evidence for beneficial effects of fatty acid supplementation is scarce. Therefore, in
this study, we aimed to determine whether omega-3 and omega-6 fatty acid concentrations are causally related to schizophrenia.

Methods
We did a two-sample Mendelian randomisation study, using deidentified summary-level data that were publicly available. Exposure-outcome relationships were evaluated using the inverse variance weighted two-sample Mendelian randomisation method using results from genome-wide association studies (GWASs) of fatty acid concentrations and schizophrenia. GWAS results were available for European (fatty acids) and European and Asian (schizophrenia)
ancestry samples. Overall age and gender information were not calculable from the summary-level GWAS results. Weighted median, weighted mode, and Mendelian randomisation Egger regression methods were used as sensitivity
analyses. To address underlying mechanisms, further analyses were done using single instruments within the FADS gene cluster and ELOVL2 gene locus. FADS gene cluster and ELOVL2 gene causal effects on schizophrenia were
calculated by dividing the single nucleotide polymorphism (SNP)-schizophrenia effect estimate by the SNP-fatty acid effect estimate with standard errors derived using the first term from a delta method expansion for the ratio estimate.
Multivariable Mendelian randomisation was used to estimate direct effects of omega-3 fatty acids on schizophrenia, independent of omega-6 fatty acids, lipoproteins (ie, HDL and LDL), and triglycerides.

Findings
Mendelian randomisation analyses indicated that long-chain omega-3 and long-chain omega-6 fatty acid concentrations were associated with a lower risk of schizophrenia (eg, inverse variance weighted odds ratio [OR] 0·83
[95% CI 0·75–0·92] for docosahexaenoic acid). By contrast, there was weak evidence that short-chain omega-3 and short-chain omega-6 fatty acids were associated with an increased risk of schizophrenia (eg, inverse variance weighted
OR 1·07 [95% CI 0·98–1·18] for α-linolenic acid). Effects were consistent across the sensitivity analyses and the FADS single-SNP analyses, suggesting that long-chain omega-3 and long-chain omega-6 fatty acid concentrations were
associated with lower risk of schizophrenia (eg, OR 0·74 [95% CI 0·58–0·96] for docosahexaenoic acid) whereas short-chain omega-3 and short-chain omega-6 fatty acid concentrations were associated with an increased risk of
schizophrenia (eg, OR 1·08 [95% CI 1·02–1·15] for α-linolenic acid). By contrast, estimates from the ELOVL2 singleSNP analyses were more imprecise and compatible with both risk-increasing and protective effects for each of the
fatty acid measures. Multivariable Mendelian randomisation indicated that the protective effect of docosahexaenoic acid on schizophrenia persisted after conditioning on other lipids, although evidence was slightly weaker (multivariable inverse variance weighted OR 0∙84 [95% CI 0∙71–1∙01]).

Interpretation
Our results are compatible with the protective effects of long-chain omega-3 and long-chain omega-6 fatty acids on schizophrenia, suggesting that people with schizophrenia might have difficulty converting short-chain polyunsaturated fatty acids to long-chain polyunsaturated fatty acids. Further studies are required to determine whether long-chain polyunsaturated fatty acid supplementation or diet enrichment might help prevent onset of schizophrenia.

Original languageEnglish
Pages (from-to)1062-1070
Number of pages9
JournalLancet Psychiatry
Volume8
Issue number12
DOIs
Publication statusPublished - 1 Nov 2021

Bibliographical note

Funding Information:
DM has a patent application (UK Patent Application number 1919155.0 for biomarkers to predict psychosis) pending. DM is also a Fellow on the Irish Clinical Academic Training Programme, which is supported by the Wellcome Trust and the Health Research Board (grant number 203930/B/16/Z), the Health Service Executive National Doctors Training and Planning, and the Health and Social Care, Research and Development Division, Northern Ireland. MCB is supported by a UK Medical Research Council Skills Development Fellowship (grant number MR/P014054/1). RC is supported by the Wellcome Trust (grant number WT 212557/Z/18/Z). All other authors declare no competing interests.

Funding Information:
This study was supported by the National Institute for Health Research (NIHR) Biomedical Research Centre at University Hospitals Bristol and Weston NHS Foundation Trust and the University of Bristol. The views expressed are those of the authors and not necessarily those of the NIHR or the UK Department of Health and Social Care.

Funding Information:
This study was supported by the National Institute for Health Research (NIHR) Biomedical Research Centre at University Hospitals Bristol and Weston NHS Foundation Trust and the University of Bristol. The views expressed are those of the authors and not necessarily those of the NIHR or the UK Department of Health and Social Care.

Publisher Copyright:
© 2021 Elsevier Ltd

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