Identification of potential drug targets for delirium from genetic insights: a Mendelian randomization study

Delirium, a prevalent acute cerebral disorder, currently lacks effective pharmacological interventions despite its substantial clinical impact. Leveraging genetic insights represents a valuable approach for advancing therapeutic discovery. This study used Mendelian randomization (MR) to systematically screen druggable genes and prioritize genetic targets for delirium. Among 5,883 druggable genes examined, we identified 11 genes with causal evidence supporting their role in delirium susceptibility, of which 5 were further supported by summary-data-based MR (SMR) and HEIDI tests. PSORS1C3 demonstrated significant genetic colocalization with delirium risk (PP.H4 = 0.746), strongly implicating its potential causal role. We also conducted an exploratory two-step MR mediation analysis and found that the genetically proxied expression of POU5F1 and PSORS1C3 may reduce delirium risk potentially by regulating white matter structural connectivity between the left hemisphere salience/ventral attention network and the default mode network. However, these mediation findings are preliminary and require validation in independent cohorts with non-overlapping samples. In conclusion, this study prioritizes PSORS1C3 and POU5F1 as high-confidence candidate genes for delirium susceptibility, providing a genetic foundation for future functional studies and guiding subsequent drug repurposing investigations. • PSORS1C3 and POU5F1 are prioritized as candidate drug targets for delirium. • Mendelian randomization and colocalization support a causal role for PSORS1C3. • Gene expression may influence delirium via white matter connectivity pathways. • These findings provide a genetic basis for future drug repurposing in delirium.