A longitudinal study of CLDN5 DNA methylation and PTSD

Area of Science:

• Neuroscience
• Genetics
• Psychiatry

Background:

• Posttraumatic stress disorder (PTSD) is linked to cognitive decline and neurodegeneration.
• Blood-brain barrier (BBB) dysfunction, involving claudin-5 (CLDN5), is a hypothesized mechanism.
• Previous studies linked CLDN5 DNA methylation (DNAm) in blood to trauma exposure and PTSD severity.

Purpose of the Study:

• To investigate if CLDN5 DNAm in blood predicts future PTSD symptom severity.
• To examine the association of CLDN5 DNAm with future neurofilament light (NFL) levels, cognitive performance, and CLDN5 RNA expression.
• To explore the role of BBB integrity in PTSD pathophysiology.

Main Methods:

• Longitudinal study of 221 trauma-exposed Veterans followed for an average of 5.6 years.
• Assessed PTSD symptoms, collected blood samples for DNAm and RNA analysis at two time points.
• Administered neuropsychological tests at follow-up to assess cognitive function.

Main Results:

• Baseline CLDN5 DNAm at cg21872764 predicted increased PTSD symptom severity at follow-up.
• CLDN5 DNAm at cg21872764 and cg00804504 were associated with future CLDN5 RNA expression.
• CLDN5 DNAm at cg16773741 predicted working memory performance, but no loci were associated with NFL levels.

Conclusions:

• CLDN5 DNAm in blood is associated with worsening PTSD symptoms and cognitive function in Veterans.
• These findings support the hypothesis that BBB disruption is involved in PTSD pathology.
• This research may help elucidate the biological basis of PTSD and its comorbidity with neurodegenerative disorders.