Integrative Mendelian randomization analysis to identify causal plasma proteins and therapeutic targets for delirium

Introduction

This study aims to identify potentially causal circulating proteins and novel drug targets for delirium using a Mendelian randomization (MR)-based analytical framework and various bioinformatics and genomics methods.

Material and methods

Large-scale two-sample MR was employed to estimate the effects of thousands of plasma proteins on delirium. Additional analysis included Bayesian Colocalization, Steiger filtering, protein-altering variant assessment, and mapping of expression quantitative trait loci (eQTL) to protein quantitative trait loci (pQTL). Protein-protein interaction (PPI) networks, pathway enrichment analysis, and evaluation of drug targets were conducted to identify potential therapeutic targets for delirium.

Results

Several plasma proteins were identified that show significant causal effects on delirium. Bayesian Colocalization confirmed that these proteins share a common genetic architecture with delirium-associated loci. Steiger filtering analysis validated the direction of causality. Assessment of protein-altering variants and eQTL-pQTL mapping provided further evidence supporting the MR findings. PPI networks and pathway enrichment analysis revealed involvement in key biological processes and pathways related to brain function and neuroinflammation. Several proteins were identified as potential therapeutic targets, offering new avenues for prevention and treatment of delirium.

Conclusions

This study identifies several plasma proteins that have a significant causal relationship with delirium, suggesting their potential as biomarkers and therapeutic targets. Our comprehensive analysis using MR, Colocalization, and other bioinformatics approaches strengthens the evidence for these associations. The findings enhance our understanding of the molecular mechanisms underlying delirium and highlight new targets for intervention, which could lead to improved prevention and treatment strategies for this condition.