The identification of plasma and cerebrospinal fluid metabolites causally associated with mental disorders from a genetic perspective.

BACKGROUND

Metabolomics research is a promising orientation for the diagnosis and intervention of several diseases, and observational studies have found many metabolic profiles to be associated with mental disorders. However, the causal relationship between plasma and cerebrospinal fluid (CSF) metabolites and mental disorders has not been established.

METHODS

We identified independent genetic variants associated with plasma, CSF metabolites, and mental disorders from pooled data in the published Genome-wide association studies (GWASs) and performed Mendelian randomization (MR) to investigate causal relationships. Genetic information on the screened mental disorders were derived from separate GWAS data sources as exploratory and validation datasets. Inverse variance weighting (IVW) was adopted as the primary method for MR analysis. We also applied sensitivity analyses to examine the reliability of the MR analysis results. Further enrichment analyses provided a deeper insight into the biological mechanisms of the three mental disorders.

RESULT

A dual analysis of the exploratory and validation datasets identified eight plasma metabolites and three CSF metabolites causally associated with MDD, two plasma metabolites and one CSF metabolite causally associated with anxiety disorders, and four plasma metabolites and two CSF causally associated with ASD. Horizontal pleiotropy and heterogeneity tests indicate the validity of our MR studies. Enrichment analysis uncovered metabolic pathways associated with disease.

CONCLUSION

Our study identified plasma and cerebrospinal fluid metabolites that were causally associated with 3 mental disorders. Characterization of disease-associated metabolites not only deepens the understanding of pathological mechanisms, but also supports clinical diagnosis and prognosis.