FKBP5 methylation, temperament, and chronotype in adolescent posttraumatic stress disorder: a preliminary case–control study

Abstract

ABSTRACT Background: Adolescents with posttraumatic stress disorder (PTSD) may show stress-system, personality, and circadian vulnerabilities, but these domains have rarely been examined together. Methods: In this exploratory case–control study, 36 newly diagnosed adolescents with DSM-5 PTSD, unmedicated at enrolment, and 36 trauma-unexposed controls (12–18 years) were assessed; diagnoses were confirmed with the K-SADS-PL. Symptom severity, temperament and character, and chronotype were measured with the Child PTSD Symptom Scale, the Junior Temperament and Character Inventory-Revised, and the Children’s Chronotype Questionnaire. FKBP5 intron 7 methylation was assessed qualitatively at seven CpG sites by Sanger sequencing of bisulfite-converted PCR products. Results: Methylation positivity was observed in 27.8% of adolescents with PTSD and in 8.3% of controls (RR = 3.33, 95% BCa CI [0.96, 12.40]), a difference not robust across analytic approaches and reported as an effect-size estimate. The PTSD group showed higher Harm Avoidance, lower Self-Directedness and Cooperativeness, and greater eveningness. In multivariable analyses, lower Self-Directedness was independently associated with greater symptom severity (β = −.44), whereas methylation positivity showed a smaller association (β = .35; R² = .470) that did not persist under penalised estimation in the logistic model of case status. Conclusions: Methylation positivity and reduced Self-Directedness co-occurred with higher symptom burden. Because the controls were trauma-unexposed rather than trauma-exposed without PTSD, these differences distinguish adolescents with PTSD from trauma-naïve peers rather than marking PTSD specifically, and the qualitative assay indexes detectable methylation rather than methylation level. Replication with quantitative methylation measures, FKBP5 rs1360780 genotyping, trauma-exposed controls, and HPA-axis biomarkers is needed.