Association Between BDNF DNA Methylation and PTSD: A Systematic Meta-Analysis of Human Case–Control Studies

Although there is conflicting quantitative data, the pathophysiology of post-traumatic stress disorder (PTSD) has been linked to epigenetic modification of brain-derived neurotrophic factor (BDNF). For making clear how BDNF promoter DNA methylation relate to PTSD, we did this first meta-analysis. Methods: Four case-control studies (617 PTSD patients and 518 controls) published before December 2025 was found from PubMed, Web of Science, CNKI, and Wanfang. Using RevMan 5.4 to do sensitivity analyses, subgroup analyses (promoter I vs. IV), and random-effects meta-analyses. The Newcastle—Ottawa Scale (NOS) was applied for assessing the quality of methods. Results: Pooled BDNF methylation was significantly lower in PTSD than in controls (SMD = − 3.45, 95%CI(-4.45,-2.45), P<0.01), but heterogeneity was high. Subgroup analyses revealed a robust hypomethylation signal for promoter IV, whereas promoter I data showed opposite directional effects and substantial inter-study variance; the combined promoter-I estimate crossed the null line. Sensitivity analyses—alternating effect models, excluding the largest study, and leave-one-out iterations—yielded consistent P < 0.05, indicating a stable overall effect. Funnel-plot asymmetry suggested possible publication bias. Conclusions: The potential of BDNF promoter IV hypomethylation as a peripheral epigenetic biomarker is supported by its continuous association with human PTSD. But for promoter-I part, the findings still not so clear and need bigger studies with proper medicine control to make sure.