Circulating metabolite abundances associated with risks of bipolar disorder, schizophrenia, and depression: a Mendelian randomization study

Abstract

BackgroundPreventive measures and treatments for psychiatric disorders are limited. Circulating metabolites are potential candidates for biomarker and therapeutic target identification, given their measurability and essential roles in biological processes. MethodsLeveraging large-scale genome-wide association studies, we conducted Mendelian randomization (MR) analyses to assess the associations between circulating metabolite abundances and the risks of bipolar disorder, schizophrenia, and depression. Genetic instruments were selected for 94 metabolites measured in the Canadian Longitudinal Study of Aging (N=8,299) cohort. We repeated MR analyses based on the UK Biobank, INTERVAL, and EPIC-Norfolk studies. ResultsAfter validating MR assumptions and colocalization evidence, we found that a one standard deviation (SD) increase in genetically predicted circulating abundances of eicosapentaenoate (EPA) and docosapentaenoate (n3 DPA) was associated with odds ratios (ORs) of 0.72 (95% CI: 0.65-0.79) and 0.63 (95% CI: 0.55-0.72) for bipolar disorder, respectively. Genetically increased Ω-3 unsaturated fatty acids abundance and Ω-3-to-total fatty acids ratio, as well as genetically decreased Ω-6-to-Ω-3 ratio were negatively associated with the risk of bipolar disorder in the UK Biobank. Genetically increased circulating abundances of three N-acetyl-amino acids were associated with an increased risk of schizophrenia with a maximum OR of 1.31 (95% CI: 1.18-1.44) per one SD increase. Furthermore, a one SD increase in genetically predicted circulating abundance of hypotaurine was associated with an OR of 0.85 (95% CI: 0.78-0.93) for depression. ConclusionsThe biological mechanisms underlying Ω-3 unsaturated fatty acids, NAT8-catalyzed N-acetyl-amino acids, and hypotaurine warrant exploration to identify new biomarkers and potential therapeutic targets.