Causal links between mitochondrial genes, cerebrospinal fluid metabolites, and delirium: a mendelian randomization study

Mitochondrial dysfunction plays a crucial role in neuropsychiatric disorders, including delirium.To explore the causal links between mitochondrial-related druggable genes, cerebrospinal fluid metabolites, and delirium.Summary-level data on mitochondrial-related druggable genes, expression quantitative trait loci (eQTLs), 338 cerebrospinal fluid (CSF) metabolites, and delirium data were obtained from publicly accessible genome-wide association studies. A two-sample Mendelian randomization (MR) was applied to assess the causal effects of blood cis-eQTL of mitochondrial-related druggable genes on delirium. Sensitivity analyses were also undertaken to ensure the MR results' reliability. We assessed whether cerebrospinal fluid metabolites mediate the causal relationship between druggable mitochondrial genes and delirium.A total of 12 mitochondrial-related druggable genes (8 protective and 4 risk) were identified to be associated with delirium risk (<i>p</i> < 0.05). Furthermore, 20 CSF metabolites were significantly associated with delirium, 9 positively and 11 negatively. Sensitivity analyses showed no evidence of heterogeneity or horizontal pleiotropy. Mediation analysis indicated that 3-hydroxyoctanoate partially mediated the causal association between sterol carrier protein 2 (SCP2) and delirium, accounting for approximately 19.23% of the total effect.The present work reveals that mitochondrial-related genes and CSF metabolites may play causal roles in delirium and highlights SCP2-3-hydroxyoctanoate as a novel molecular axis. These findings expand current knowledge of delirium pathogenesis and offer a potential molecular target for diagnosis and therapy. Further experimental validation and population-diverse studies are needed to confirm these findings.