Unraveling Tissue-Specific Molecular Signatures and Convergent Pathway Enrichments in Suicidal Behavior

Area of Science:

• Neuroscience
• Genetics
• Psychiatry

Background:

• Suicide is a major global health concern with poorly understood biological underpinnings.
• Identifying molecular mechanisms is crucial for developing objective biomarkers and effective interventions for suicide prevention.

Purpose of the Study:

• To investigate gene expression patterns in peripheral blood and postmortem brain tissue associated with suicidal thoughts and behaviors.
• To identify molecular signatures that may serve as biomarkers or therapeutic targets for suicide.

Main Methods:

• Transcriptomic profiling of peripheral blood (n=264) and postmortem brain tissue (dorsolateral prefrontal cortex, subgenual anterior cingulate cortex; n=249).
• Longitudinal modeling to predict suicide attempts.
• Gene co-expression network analysis.
• Cross-tissue comparison of molecular signatures.

Main Results:

• Peripheral blood showed broad transcriptional changes linked to suicidal behaviors, involving immune and inflammatory processes.
• Longitudinal analysis identified gene modules predicting future suicide attempts, related to apoptosis, mitochondrial function, and immune regulation.
• Postmortem brain tissue revealed suppressed neuroimmune activity, with distinct suicide-associated modules in synaptic plasticity, oxidative stress, and neuroimmune function.
• Minimal gene-level overlap but shared pathway themes (immune, sensory, cellular stress) between blood and brain.

Conclusions:

• Suicide is associated with distinct yet functionally convergent transcriptional alterations across brain and blood.
• Findings provide insights into the biological architecture of suicide.
• This work lays the groundwork for novel biomarkers and therapeutic targets to improve suicide prevention and treatment.