Metabolomic investigation of major depressive disorder identifies a potentially causal association with polyunsaturated fatty acids

作者：E. Davyson, Xueyi Shen, D. Gadd, E. Bernabéu, R. Hillary, D. McCartney, M. Adams, R. Marioni, A. McIntosh · 发表于：Biological Psychiatry · 年份：2023 · DOI：10.1016/j.biopsych.2023.01.027 · 被引用次数：66 · 研究领域：Medicine

Background: Metabolic differences have been reported between individuals with and without Major Depressive Disorder (MDD), but their consistency and causal relevance has been unclear. Methods: We conducted a metabolome-wide association study of MDD with 249 metabolomic measures available in UK Biobank (N = 29, 757). We then applied 2-sample bidirectional Mendelian Randomisation (MR) and colocalization analysis to identify potentially causal relationships between each metabolite and MDD. Results: One hundred and ninety-one metabolites tested were significantly associated with MDD (PFDR < 0.05), which reduced to 129 after adjustment for likely confounders. Lower abundance of Omega-3 fatty acid measures and a higher Omega-6: 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 FADS gene cluster. Post-hoc MR of gene-transcript abundance within the FADS cluster demonstrated a causal association with MDD. In contrast, colocalization analysis did not suggest a single causal variant for both transcript abundance and MDD liability, but the likely existence of two variants in LD with one another. Conclusion: Our findings suggest that decreased Docosahexaenoic Acid and increased Omega-6: Omega-3 fatty acids ratio may be causally related to MDD. These findings provide further support fo...