Replication of claudin-5 epigenetics in association with PTSD severity in the VA Million Veteran Program

Posttraumatic stress disorder (PTSD) is associated with neurocognitive decline and disease but the pathways linking these conditions are unclear. Recent preclinical and clinical research focused on depression and PTSD has suggested that the claudin-5 (CLDN5) protein, which comprises the tight junction proteins that seal the blood brain barrier, may relate to susceptibility to these stress-related conditions and associated neuropathology. We evaluated if we could replicate associations between CLDN5 DNA methylation and PTSD symptom severity in a large cohort of 22,835 Veterans enrolled in the VA Million Veteran Program. In the full cohort, we found evidence of replication for cg17411190 after adjustment for multiple testing (B = 2.76E-05, β = .017, p = .001, p-adj = .026), with cg05460329 replicating at the level of nominal significance (p = .023). In age-stratified analyzes, there was replication at cg17411190 and cg21872764 (ps = .046 and .009, respectively) at the nominally significant level in the age 65+ group. All associations replicated the effect directions seen in prior work. Results highlight the relevance of CLDN5 epigenetics for stress-related psychopathology and suggest that methylation of this gene in blood may be a useful biomarker for symptom severity and could potentially help to explain the association between PTSD and neuropathology.