Identification of Potential Drug Targets for Generalized Anxiety Disorder: A Mendelian Randomization Study Based on Druggable Genes

Introduction: Generalized anxiety disorder (GAD) is a prevalent and intricate mental disorder that significantly impairs the quality of life of patients. Currently, the exact etiology of GAD remains incompletely understood. Consequently, the discovery of novel drug targets for GAD is highly important. Methods: We obtained cis-eQTL data of druggable genes from the eQTLGen Consortium as the exposure data and GWAS data of GAD from the FinnGen Database as the outcome. The impact of druggable genes on GAD was simulated through Mendelian randomization analysis. Subsequently, a colocalization analysis was conducted to calculate the probability of shared pathogenic variants between the cis-eQTLs of druggable genes and GAD. To further validate our findings, a summary data-based Mendelian randomization (SMR) analysis was carried out. Results: Mendelian randomization (MR) analysis identified 24 druggable genes with potential causal relationships, among which genetically predicted increased KDM5A levels were associated with a higher risk of GAD (OR=1.0991, 95% CI: 1.0021–1.2056, P=0.0451), suggesting a potential role of KDM5A gene expression in the pathogenesis of GAD. The GAD and KDM5A genes might share a causal variant. The SMR further verified the accuracy of the KDM5A gene. Discussion: MR analysis identified KDM5A as a promising therapeutic target for GAD, with additional potential from genes, like MERTK and PPT1. However, the effectiveness of the relevant drug targets requires further validation. Conclusion: This study suggested that the KDM5A gene might be a potential therapeutic target for treating GAD, providing a direction for future drug development in GAD patients.