A longitudinal study of CLDN5 DNA methylation and PTSD

Posttraumatic stress disorder (PTSD) is associated with elevated risk for cognitive decline and neurodegeneration in later life, yet the underlying biological mechanisms remain poorly understood. One hypothesized pathway involves dysfunction of the blood-brain barrier (BBB) via altered expression of claudin-5 (CLDN5), a tight junction protein key to BBB integrity. Our prior cross-sectional study found that DNA methylation (DNAm) in blood at three CLDN5 loci was associated with trauma exposure, PTSD symptom severity, and plasma neurofilament light (NFL). Building on these results, this study examined whether CLDN5 DNAm in blood predicted future PTSD symptom severity, NFL, neuropsychological performance, and CLDN5 RNA expression in blood, a possible proxy for CLDN5 in the brain. Trauma-exposed Veterans (N = 221; 174 returned for follow-up) were assessed twice over 5.6 years on average. Participants completed diagnostic interviews, provided blood samples at both timepoints, and completed a neuropsychological battery at follow-up (California Verbal Learning Test-II, Wechsler Adult Intelligence Scale and Delis-Kaplan Executive Function System subtests). Baseline CLDN5 DNAm at cg21872764 predicted increased PTSD symptom severity at follow-up, accounting for baseline PTSD symptoms (β = .128, p = .035). This probe was associated with future CLDN5 RNA expression (β= -.186, p-adj = .035) as was cg00804504 (β = .185, p-adj = .035). CLDN5 DNAm at cg16773741, linked to cognitive decline, predicted working memory performance at follow-up (β = .269, p-adj = .015). No loci were associated with NFL levels after corrections for multiple testing. Results suggest that CLDN5 DNAm is associated with increased PTSD severity over time among Veterans with substantial trauma histories and is associated with neuropsychological functioning. This raises the possibility that BBB disruption is part of PTSD pathology, which may help identify the biology underlying comorbidity between PTSD and neurodegenerative disorders.