Exploratory Analysis of Potential Causal Links Between Blood and Urine Metabolites and Psychiatric Disorders: A Bidirectional Mendelian Randomization Study

Psychiatric disorders represent biologically heterogeneous conditions for which robust molecular correlates remain elusive. While metabolic perturbations have been documented in psychiatric cohorts, whether these associations denote causal relationships or secondary downstream consequences remains unresolved. The United Kingdom Biobank (UK Biobank) has published genetic data for 35 human blood and urine metabolites, providing a research basis for studying the impact of genetics on mental illness. This study employs a two-sample bidirectional Mendelian randomization (MR) method to investigate the causal relationship between blood and urine metabolites and the most common types of psychiatric disorders, including depression, anxiety disorder (AD), generalized anxiety disorder (GAD), schizophrenia, post-traumatic stress disorder (PTSD), panic disorder (PD), somatoform disorder (SSD), and bipolar disorder (BD). Instrumental variables for blood and urine metabolites were derived from a genome-wide association study (GWAS) of 35 human blood and urine metabolites published by UK Biobank. Psychiatric disorder variables were obtained from the FinnGen consortium. A bidirectional two-sample Mendelian randomization framework was used to evaluate potential causal relationships between 35 metabolites and eight psychiatric disorders. The inverse variance-weighted (IVW) method was the primary statistical approach, with MR-Egger, weighted median (WM), simple mode and weighted mode methods enhancing accuracy. Rigorous multiple testing correction was applied. The sensitivity analyses were conducted by using Cochran’s Q test and MR-Egger intercept tests. In the forward MR analysis, several nominally significant associations were identified, including positive effects of cystatin C on depression and somatoform disorder (SSD), as well as urea on generalized anxiety disorder (GAD) and panic disorder (PD). However, none of these associations remained statistically significant after false discovery rate (FDR) correction. In the reverse MR analysis, one robust association was observed: genetic predisposition to panic disorder was significantly associated with lower triglyceride (TRIG) levels (β = −0.028, 95% CI: −0.043 to − 0.013; P < 0.001; FDR- P = 0.01). Other suggestive associations did not withstand multiple testing correction (all P < 0.05; all FDR- P > 0.05). This bidirectional MR study provides limited, exploratory evidence for potential genetic associations between circulating metabolites and psychiatric disorders. Following correction for multiple testing, only the association between genetic liability to panic disorder and triglyceride levels remained statistically significant. Our findings therefore warrant cautious interpretation. Further replication studies and mechanistic investigations are required to elucidate the biological relevance of these observations.