Transcriptomic organization of the human brain in post-traumatic stress disorder

Area of Science:

• Neurobiology
• Molecular Psychiatry
• Genetics

Background:

• Post-traumatic stress disorder (PTSD) is extensively studied neurobiologically, but its molecular underpinnings remain largely unknown.
• Understanding molecular determinants is crucial for advancing PTSD research and treatment.

Purpose of the Study:

• To investigate the molecular determinants of PTSD by analyzing gene expression in postmortem prefrontal cortex tissue.
• To identify specific genes and networks associated with PTSD pathophysiology.
• To explore potential sex differences and compare molecular profiles with major depressive disorder.

Main Methods:

• Differential gene expression and network analyses were performed on four prefrontal cortex subregions from individuals with and without PTSD.
• Integration with genome-wide association study (GWAS) data identified genetic liability.
• Transcriptomic data was compared between PTSD, major depressive disorder (MDD) cohorts, and sexes.

Main Results:

• Extensive transcriptomic landscape remodeling was observed in the prefrontal cortex of individuals with PTSD.
• A significant gene network associated with PTSD featured downregulated interneuron transcripts.
• The interneuron synaptic gene ELFN1 was identified as conferring significant genetic liability for PTSD.
• Marked transcriptomic sexual dimorphism was detected, potentially explaining higher PTSD rates in women.
• Distinct molecular profiles were observed between PTSD and MDD, despite high comorbidity.

Conclusions:

• Convergent systems-level evidence implicates specific genomic networks within the prefrontal cortex in PTSD pathophysiology.
• The identification of ELFN1 provides a novel molecular target for PTSD research.
• Transcriptomic sexual dimorphism highlights potential sex-specific mechanisms in PTSD development.