Abstract
BACKGROUND: From the pathway perspective, metabolites have the potential to improve knowledge about the aetiology of psychiatric diseases. Previous studies suggested a link between specific blood metabolites and mental disorders, but some Mendelian randomisation (MR) studies in particular are insufficient for various reasons. OBJECTIVE: This study focused on bias assessment due to interdependencies between metabolites and psychiatric mediation effects. METHODS: In a multistep framework containing network and multivariable MR, direct effects of 21 mutually adjusted metabolites on 8 psychiatric disorders were estimated based on summary statistics of genome-wide association studies from multiple resources. Robust inverse-variance weighted models were used in primary analyses. Several sensitivity analyses were performed to assess different patterns of pleiotropy and weak instrument bias. Estimates for the same phenotypes from different resources were pooled using fixed effect meta-analysis models. FINDINGS: After adjusting for mediation effects, genetically predicted metabolite levels of six metabolites of lipid, amino acid and cofactors pathways were directly associated with overall six mental disorders (attention-deficit/hyperactivity disorder, bipolar disorder, anorexia nervosa, depression, post-traumatic stress disorder and schizophrenia). Point estimates ranged from -0.45 (95% CI -0.67; -0.24, p=1.0×10(4)) to 1.78 (95% CI 0.85; 2.71, p=0.006). No associations were found with anxiety and suicide attempt. CONCLUSIONS: This study provides insights into new metabolic pathways that seems to be causally related to certain mental disorders. CLINICAL IMPLICATIONS: Further studies are needed to investigate whether the identified associations are effects of the metabolites itself or the biochemical pathway regulating the metabolites.