Convergent and Distinct Transcriptional Signatures in Suicide, Bipolar Disorder, and Major Depressive Disorder

Abstract

Globally, a person dies by suicide every 40 seconds, underscoring a major global public health concern. In the United States, suicide is the second leading cause of death among individuals aged 10-34 years. Suicide is a complex, multifactorial phenomenon influenced by genetic and epigenetic factors and is strongly associated with mood disorders, particularly major depressive disorder (MDD) and bipolar disorder (BD). However, the extent to which their molecular signatures converge or diverge across disorders and brain regions remains incompletely understood. To address this gap, we conducted a systematic literature review of suicide, MDD, and BD transcriptomic studies in accordance with PRISMA 2020 guidelines, searching PubMed, Embase, and Web of Science. Eligible studies used human postmortem brain tissue, reported a complete genome-wide transcriptomic list of differentially expressed genes (DEG), and compared suicide decedents with psychiatric non-suicide individuals diagnosed with the same underlying disorder. Regarding BD, studies comparing affected individuals to unaffected controls were included. Single-cell and peripheral-blood studies were excluded because unavailable for suicide. Curated suicide and BD DEG datasets were integrated with a published bulk transcriptomic dataset of MDD. We identified both shared and disease-specific molecular signatures across suicide, BD, and MDD, and identified DEGs shared across brain regions and those that were region-specific. A total of 276 genes were shared across all three conditions, implicating cellular stress, hypoxia (VEGFA, ADM, NDRG1, DDIT4), immune and inflammatory signaling through TNF/NF-{kappa}B (IL1B, ICAM1, NFE2L2) and IL6-JAK-STAT3 pathways (STAT3, SOCS3, IL1R1m OSMR), complement activation (CIR, SERPiNA1, LGALS3), extracellular matrix remodeling (COL4A1, SERPINH1, PLOD2), and unfolded protein response (BAG3, WFS1, MTHFD2). Suicide-associated DEGs were prominently downregulated, and involved metal-ion homeostasis, stress responses, synaptic regulation, and circadian pathways, whereas BD showed downregulation in synaptic and vesicle-related processes alongside region-specific metabolic dysregulation. MDD exhibited changes in RNA processing, ribosomal function, and protein synthesis. Genetic integration revealed that 133 genes shared between BD and MDD had gene variants associated with the corresponding condition per GWAS. Transcription factor analysis identified 20 regulatory factors with altered activity across all three conditions despite differences in their predicted downstream targets. Overall, these findings suggest that suicide, MDD, and BD share aspects of their molecular and regulatory pathophysiology while exhibiting distinct patterns, including in a region-specific manner.