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

Area of Science:

• Neuroscience
• Genomics
• Psychiatry

Background:

• Major depressive disorder (MDD) is a leading cause of suicide.
• Understanding the molecular basis of MDD and suicide risk is critical.

Purpose of the Study:

• To investigate cell type-specific gene expression in the hippocampus of individuals with MDD, comparing those who died by suicide versus other means.
• To identify molecular pathways associated with suicidality in MDD.

Main Methods:

• Transcriptome-based deconvolution of postmortem hippocampal samples from control, MDD (non-suicide), and MDD (suicide) groups.
• Single-nucleus RNA sequencing (snRNA-Seq) to establish reference gene expression profiles.
• Differential expression analysis at the cell-type level using MuSiC2 and bMIND.

Main Results:

• Identified 5 primary hippocampal cell categories: pyramidal, GABAergic, microglia, macroglia, and endothelial cells.
• Cell type-specific gene expression patterns differed significantly between MDD groups.
• Pyramidal neurons showed distinct pathway enrichments: cytoskeleton in non-suicide MDD, immune-related in suicide MDD.

Conclusions:

• Distinct cell type-specific transcriptomic profiles highlight vulnerabilities associated with suicidality in MDD.
• Findings suggest potential for targeted interventions for suicide risk mitigation in depression.