Metabolomic Investigation of Major Depressive Disorder Identifies a Potentially Causal Association With Polyunsaturated Fatty Acids

Abstract

Background: Metabolic differences have been reported between individuals with and without major depressive disorder (MDD), but their consistency and causal relevance have been unclear.

Methods: We conducted a metabolome-wide association study of MDD with 249 metabolomic measures available in the UK Biobank (n = 29,757). We then applied two-sample bidirectional Mendelian randomization and colocalization analysis to identify potentially causal relationships between each metabolite and MDD.

Results: A total of 191 metabolites tested were significantly associated with MDD (false discovery rate-corrected p < .05), which decreased to 129 after adjustment for likely confounders. Lower abundance of omega-3 fatty acid measures and a higher omega-6 to omega-3 ratio showed potentially causal effects on liability to MDD. There was no evidence of a causal effect of MDD on metabolite levels. Furthermore, genetic signals associated with docosahexaenoic acid colocalized with loci associated with MDD within the fatty acid desaturase gene cluster. Post hoc Mendelian randomization of gene-transcript abundance within the fatty acid desaturase cluster demonstrated a potentially causal association with MDD. In contrast, colocalization analysis did not suggest a single causal variant for both transcript abundance and MDD liability, but rather the likely existence of two variants in linkage disequilibrium with one another.

Conclusions: Our findings suggest that decreased docosahexaenoic acid and increased omega-6 to omega-3 fatty acids ratio may be causally related to MDD. These findings provide further support for the causal involvement of fatty acids in MDD.

Keywords: Colocalization; Depression; Fatty acids; Mendelian randomization; Metabolome; Multiomics.

Figure 1:. Adjusted MetWAS.

Standardized effect sizes for Metabolite ~ MDD + covariates. Significant associations (P_FDR < 0.05) are shaded in, and the most significant association for each metabolite group are labelled.

Figure 2:. Metabolite to MDD Mendelian Randomisation (MR) analysis.

The odds ratios of metabolite on lifetime MDD status given by the inverse variance weighted MR method, coloured by metabolite group. Significant MR findings (P_FDR < 0.05) are filled in and labelled. DHA; Docosahexaenoic Acid, Unsaturation; Degree of Unsaturation, Omega_3_pct; Omega-3 to Total Fatty Acids (%), Omega-3; Omega-3 Fatty Acids, Omega_6_by_Omega_3; Omega-6: Omega-3 Ratio.

Figure 3:. Colocalization of Docosahexaenoic Acid with MDD.

A) The association of SNVs in the FADS cluster in the Docosahexaenoic Acid GWAS. B) The association of SNVs in the FADS cluster in the MDD GWAS (Without UKB). C) The genes present in the FADS cluster. Genes colored red are those which were present in the GTEx data and consequently tested for a causal relationship with MDD in the post-hoc analysis.