Transcriptomic analysis uncovers the shared and unique biological foundations acrossSchizophrenia, Bipolar and Major Depressive Disorders
Authors: Priyanka Priyanka , Kumar Rajesh , Rana Sandeep Singh 
Published: January 2025

Psychiatric disorders, including Schizophrenia (SCZ), Bipolar Disorder (BD), and Major Depressive Disorder (MDD), represent complex neuropsychiatric conditions with significant overlap in clinical presentation yet distinct pathophysiological mechanisms. Understanding the molecular underpinnings of major psychiatric disorders remains a significant challenge in neuroscience. This study conducted a comprehensive transcriptomic analysis integrating publicly available 538 RNA-seq datasets from post-mortem samples across multiple brain regions to elucidate shared and unique biological foundations underlying these disorders. We employed systematic bioinformatic approaches to analyze differential gene expression patterns and pathway dysregulation across the disorders and the brain regions. ​​The identified differentially expressed genes were further analyzed for shared biological pathways, candidate drugs, and transcription factors. Protein-protein interaction (PPI) network analysis and transcription factor ranking were performed to understand the regulatory mechanisms governing unique and shared molecular behaviors across these disorders. Our findings revealed distinct transcriptional signatures with notable overlap between SCZ and BD, identifying 373 shared differentially expressed genes (DEGs) and 12 common hub genes. BD exhibited the highest number of unique DEGs, followed by SCZ and MDD, suggesting disorder-specific molecular mechanisms. Brain region-specific analyses demonstrated distinctive transcriptional patterns, particularly in the hippocampus and DLPFC, highlighting the spatial heterogeneity of gene expression changes. Pathway analysis uncovered disorder-specific dysregulation patterns: MDD showed predominant alterations in stress response and metabolic pathways; BD demonstrated robust immune system activation and cellular growth signaling perturbations; and SCZ exhibited a complex interplay of immune dysregulation, oxidative stress, and metabolic disruptions. Network analysis identified key transcription factors, including STAT3, NF-κB, and CREB1, as major regulators of the disease-specific gene expression patterns. Notably, our drug-gene interaction analysis using DGIdb revealed promising therapeutic implications, with key genes like SERPINA3 interacting with antipsychotic agents, and inflammatory mediators such as IL6 and CCL2 showing potential interactions with immunomodulators. These findings suggest novel drug repurposing strategies and targeted therapeutic approaches for psychiatric disorders. These findings provide crucial insights into the molecular underpinnings of major psychiatric disorders, revealing both shared biological mechanisms and disorder-specific pathways. The identification of common hub genes and key transcription factors suggests potential therapeutic targets for intervention. Furthermore, our results emphasize the importance of considering both shared and unique molecular signatures in developing targeted treatment strategies for psychiatric disorders, potentially leading to more personalized therapeutic approaches.