Omega- 3 Fatty Acids and Major Depression: A Mendelian Randomization Study

Abstract

Objective: Omega-3 fatty acids have been implicated in the aetiology of depressive disorders, though trials supplementing omega 3 to prevent depression have so far been unsuccessful. Whether this association is causal remains unclear. Methods: We used two sample Mendelian Randomization (MR) to help inform causal inference. 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) Major Depressive Disorder (MDD, n=430,775; cases=116,209; controls=314,566) and recurrent Major Depression (rMDD, n=80,933; cases=17,451; controls=62,482) genome wide association studies (GWAS) were used as outcomes. Multivariable (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 (CHARGE, n=8,866). Genetic colocalization analyses were used to approiximate the probability of a shared underlying causal variant between traits. Results: Genetically predicted total omega-3 fatty acids reduced the odds of MDD (ORIVW 0.96 per standard deviation (SD, i.e. 0.22mmol/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 (OREPA 0.92; 95% CI 0.88 to 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 inconclusive, meaning genomic confounding could not be fully excluded. Conclusions: 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 the importance of adequate power to detect modest effect sizes.

Very low Omega‐3 Index in young healthy students from Palestine

“…Seafood‐derived long‐chain omega‐3 (n3) polyunsaturated fatty acids (PUFA), such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), have been associated with several health benefits, including reduced risk of coronary heart disease, cardiovascular disease, and all‐cause mortality (Harris et al, 2018), as well as improved brain development (McNamara & Carlson, 2006) or cognitive function (Satizabal et al, 2022), and reduced major depression (Carnegie et al, 2022) and inflammatory conditions (Calder, 2017). Scientific societies recommend 2–3 portions of fish per week to meet the demand of long‐chain n3 PUFA (Rimm et al, 2018; U.S. Department of Health and Human Services, 2005).…”