Omega-3 fatty acids and major depression: a Mendelian randomization study

Abstract

Omega-3 fatty acids have been implicated in the aetiology of depressive disorders, though trials supplementing omega-3 to prevent major depressive disorder (MDD) have so far been unsuccessful. Whether this association is causal remains unclear. We used two sample Mendelian randomization (MR) to investigate causality. Genetic variants associated with circulating omega-3 and omega-6 fatty acids in UK Biobank (UKBB, n = 115,078) were selected as exposures. The Psychiatric Genomics Consortium (PGC) genome-wide association studies (GWAS) of MDD (n = 430,775; cases = 116,209; controls = 314,566) and recurrent depression (rMDD, n = 80,933; cases = 17,451; controls = 62,482), were used as outcomes. Multivariable MR (MVMR) models were used to account for biologically correlated lipids, such as high- and low-density cholesterol and triglycerides, and to explore the relative importance of longer-chain omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) using data from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE, n = 8866). Genetic colocalization analyses were used to explore the presence of a shared underlying causal variant between traits. Genetically predicted total omega-3 fatty acids reduced the odds of MDD (OR_IVW 0.96 per standard deviation (SD, i.e. 0.22 mmol/l) (95% CIs 0.93-0.98, p = 0.003)). The largest point estimates were observed for eicosapentaenoic acid (EPA), a long-chain omega-3 fatty acid (OR_EPA 0.92; 95% CI 0.88-0.96; p = 0.0002). The effect of omega-3 fatty acids was robust to MVMR models accounting for biologically correlated lipids. 'Leave-one-out' analyses highlighted the FADS gene cluster as a key driver of the effect. Colocalization analyses suggested a shared causal variant using the primary outcome sample, but genomic confounding could not be fully excluded. This study supports a role for omega-3 fatty acids, particularly EPA, in the aetiology of depression, although pleiotropic mechanisms cannot be ruled out. The findings support guidelines highlighting the importance of EPA dose and ratio for MDD and question whether targeted interventions may be superior to universal prevention trials, as modest effect sizes will limit statistical power.

Fig. 1. Overview of omega-3 and omega-6 fatty acid metabolism.

Omega 3- and -6 fatty acid metabolic pathway, including some common dietary sources, shared enzymes involved in desaturation and elongation, and some derived products of inflammatory importance. Specific Omega-6 and Omega-3 fatty acids included as exposures in MR analyses (i.e. EPA, DHA, and LA) are highlighted in a biological context. Total Omega-3 and -6 fatty acid measurements include measures of all the fatty acids of these subtypes. Omega-3% is a further derived measurement of the percentage of Omega-3 fatty acids to total fatty acids. The pathway, products and food sources are oversimplified for clarity. Although many of the omega-6 fatty acid AA derivatives are pro-inflammatory, and more of the omega-3 fatty acid EPA and DHA derivatives are considered lower inflammatory or anti-inflammatory, this is also an oversimplification.

Fig. 2. An overview of GWAS datasets used for exposures and outcomes.

Further information on the GWAS datasets, including access, is given in supplementary material (S2). As our main exposure GWASs were from UK Biobank, our primary outcome sample was a GWAS with UK Biobank participant data excluded. The complete MDD GWAS sample was used for validation, to check for bias due to sample overlap, and to maximize analytical power (results provided in supplementary material, S5). GWAS summary statistics for the majority of studies are freely available, see supplementary material.

Fig. 3. Overview of MR methods.

An overview of MR methods used in this paper, with an explanation of rationale. Consistency of MR effect estimates between methods increases the strength of findings.

Fig. 4. MR results for multiple fatty acid exposures on MDD (n = 480,539) and rMDD (n = 80,933).

MR results for MDD and rMDD outcomes using different methods are shown for each fatty acid exposure. All exposure SNPs and SNP-exposure estimates are derived from UKBB, except EPA, which uses effect sizes derived from the CHARGE EPA GWAS [48] (see Supplementary Methods 1). MR estimates restricted to the FADS SNP have been omitted for LA and omega 6 due to the inconsistency between estimates derived from other MR methods, which suggest that the results may be driven by pleiotropy (see discussion for more details). In addition to being potentially misleading, the impact of the wide confidence intervals on-axis measurements hinders the visualization of remaining results.