Deconvolution-Based Transcriptomic Analysis in the Hippocampus Reveals Cell Type-Specific Risk Genes and Pathways Associated With Depression and Suicide.

Background: Major depressive disorder (MDD) is a prevalent mental health condition with the highest associated suicide risk among major psychiatric disorders. Understanding the molecular and cellular mechanisms is crucial for assessing the risk of MDD and associated suicide. Methods: In this study, transcriptome-based deconvolution was applied to human postmortem hippocampal samples from nonpsychiatric control subjects ( Results: The snRNA-Seq analysis identified 11 major cell types in the hippocampus, which were consolidated into 5 primary categories: pyramidal, GABAergic (gamma-aminobutyric acidergic), microglia, macroglia, and endothelial cells. Variability in the cell-type proportions was noted among the sample groups, and the gene expression deconvolution showed distinct patterns among cell types and sample groups. Differential expression analysis at the cell-type level identified more differentially expressed genes than the bulk transcriptome, with variations across comparisons and cell types. Notably, pyramidal neurons displayed significant contrasts between D-S and D+S subjects; the former group exhibited enrichment in cytoskeleton-related pathways and molecular functions, while the latter demonstrated a prevalence of immune-related terms. Conclusions: The distinct cell type-specific transcriptomic patterns, gene networks, and pathways reveal critical vulnerabilities associated with suicidality in individuals with MDD. These findings underscore the potential for targeted interventions aimed at these specific molecular pathways to mitigate suicide risk in individuals with depression.