From Clinic to Mechanisms: Multi-Omics Provide New Insights into Cerebrospinal Fluid Metabolites and the Spectrum of Psychiatric Disorders.

Cerebrospinal fluid (CSF) is crucial in maintaining brain homeostasis by facilitating waste clearance, nutrient transport, and immune signaling. However, the links between CSF metabolites and psychiatric disorders, as well as the underlying mechanisms, remain largely unexamined. We conducted a bidirectional two-sample Mendelian randomization analysis to investigate potential causal relationships between CSF metabolites and 12 psychiatric disorders. Summary data for psychiatric disorders were sourced from the Psychiatric Genomics Consortium, while information on CSF metabolites was derived from two studies within the Wisconsin Alzheimer's Disease cohort. Causal estimates and pleiotropy were assessed using several robust methods, including inverse-variance-weighted (IVW) analysis, weighted median analysis, MR-Egger regression, and the MR-Egger test. Furthermore, a transcriptome-wide association study was conducted to explore potential mechanisms and shared etiologies between CSF metabolites and psychiatric disorders. The genetic risk of eating disorders (ED) can be increased by leucine (OR = 1.55, 95% CI: 1.21-1.97, P = 4.35 × 10⁻), salicylate (OR = 1.03, 95% CI: 1.01-1.04, P = 4.95 × 10⁻), and 1-methylnicotinamide (OR = 1.06, 95% CI: 1.03-1.09, P = 6.94 × 10⁻), while methylmalonate may reduce ED risk (OR = 0.95, 95% CI: 0.93-0.98, P = 1.31 × 10⁻). Similarly, the risk of schizophrenia (SCZ) may be reduced by threonate (OR = 0.93, 95% CI: 0.89-0.97, P = 1.98 × 10⁻), oxalate (OR = 0.94, 95% CI: 0.90-0.97, P = 3.15 × 10⁻), phenyllactate (OR = 0.96, 95% CI: 0.94-0.98, P = 2.23 × 10⁻), N-acetylglucosamine (OR = 0.98, 95% CI: 0.97-0.99, P = 3.57 × 10⁻), and citramalate (OR = 0.98, 95% CI: 0.98-0.99, P = 5.78 × 10⁻). Conversely, SCZ may upregulate gamma-glutamylleucine (β = 0.08, P = 1.97 × 10⁻) and O-sulfo-L-tyrosine (β = 0.06, P = 1.25 × 10⁻), while downregulating gamma-glutamylphenylalanine (β = - 0.50, P = 1.16 × 10⁻). Signal pathways related to the mechanistic target of the rapamycin (mTOR), post-translational protein modifications, and immune regulation may mediate the causal relationship of CSF metabolites on ED and SCZ. We identified a casual genetic causal relationship between CSF metabolites and both ED and schizophrenia SCZ, which is potentially mediated by pathways related to energy metabolism, post-translational modifications, and immune regulation.