Systematic druggable genome-wide Mendelian randomization identifies therapeutic targets for major depressive disorder

Abstract

BACKGROUND: The occurrence of major depressive disorder is typically associated with genetic and environmental factors. Currently, the diagnosis of major depressive disorder mainly relies on clinical interviews and symptom assessments, lacking clear and reproducible biological markers. This can lead to misdiagnosis and missed diagnoses, delaying the timing of treatment. OBJECTIVE: To identify druggable genes that may act as potential therapeutic targets for major depressive disorder by conducting comprehensive genome-wide Mendelian randomization analysis. METHODS: By integrating expression quantitative trait locus (eQTL) data and protein quantitative trait locus (pQTL) data from pharmacologically actionable genes with genome-wide association study (GWAS) data on major depressive disorder (including 177 377 cases and 445 321 controls), Mendelian randomization analysis was conducted to identify druggable genes that have a causal relationship with major depressive disorder. Additionally, enrichment analysis, protein-protein interaction network construction, drug target identification, and molecular docking simulations were performed to further explore potential therapeutic strategies. RESULTS AND CONCLUSION: A total of 4 394 druggable genes were analyzed, and 21 druggable genes considerably associated with major depressive disorder were identified. Bayesian colocalization analysis indicated that BTN3A3, CISD1, and PSMB4 had posterior probabilities of hypothesis 4 (H4.abf) > 0.5, supporting the possibility of shared causal variants. GO enrichment analysis mainly involved 'antigen processing and presentation', 'protein degradation and processing', 'mitochondrial outer membrane', and 'immune receptor activity' pathways related to major depression. Protein-protein interaction network analysis showed moderate connectivity among the identified genes (21 nodes, 14 edges). Drug target identification determined gemcitabine (CID 60750), fucose (CID 17106), and isococculidine (CID 2826) as main candidate compounds, which had strong associations with several key genes. Molecular docking analysis revealed stable drug-protein interactions, with isococculidine showing the most stable binding energy (-52.74 kJ/mol) with BTN3A3. In conclusion, Mendelian randomization combined with genomics and structural biology analysis provides valuable decision-making basis for target prioritization and drug repurposing, offering new ideas and directions for efficient utilization of basic research resources and drug development for major depressive disorder.

1. Introduction

Major depressive disorder is a complex neuropsychiatric disease characterized by persistent low mood, loss of interest or pleasure, and recurrent suicidal ideation, often accompanied by significant emotional, cognitive, and physical dysfunction [1]. These symptoms not only severely affect patients' quality of life but may also exacerbate other diseases and social adaptation difficulties, further expanding the overall burden of the disease [2]. Currently, major depressive disorder has been listed as one of the most disabling diseases globally, with its prevalence continuously rising, especially after the COVID-19 pandemic, when the global number of depression patients rapidly increased to approximately 246 million [3].

The occurrence of major depression is usually associated with genetic and environmental factors [4]. At present, the diagnosis of major depressive disorder still mainly relies on clinical interviews and symptom assessments, lacking clear and reproducible biological markers, which can easily lead to misdiagnosis and missed diagnosis, delaying treatment opportunities [5]. Major depressive disorder has become a global public health challenge due to its high prevalence, high disability, and high recurrence rate, imposing a heavy burden on social and economic systems [6]. The pathophysiological mechanism of major depressive disorder is extremely complex, and the etiological mechanism has not been fully elucidated to date. Studies have shown that the occurrence of major depression may involve multiple intersecting pathways, including neuroinflammation, hypothalamic-pituitary-adrenal axis dysfunction, and neuroplasticity impairment [7-9].