The Epigenetic Landscape of Borderline Personality Disorder: Insights from a Systematic Review.

Background/Objectives: Borderline personality disorder (BPD) is a serious psychiatric condition characterized by affective instability, impulsivity, and self-harming behaviors. Increasing evidence suggests that epigenetic mechanisms, especially DNA methylation, may mediate the interaction between genetic susceptibility and adverse environmental factors. This systematic review aimed to synthesize available findings on DNA methylation in BPD, including candidate gene studies and epigenome-wide association studies (EWAS). Methods: We conducted a systematic search of PubMed, Embase, and Scopus databases following PRISMA guidelines. Eligible studies (N = 19) included original research examining DNA methylation in individuals with BPD, assessed either through candidate gene approaches or genome-wide platforms. Data were extracted regarding study design, sample characteristics, psychometric instruments, genes, CpG sites analyzed, and main findings. Results: Inconsistent associations were found between BPD and altered methylation of several candidate genes, such as NR3C1, FKBP5, BDNF, DRD2, HTR2A, and COMT. Differential methylation was often linked to early-life adversities and symptom severity. EWAS also identified new loci, including APBA3, MCF2, PXDN, and OPRK1. Across studies, methodological heterogeneity and small sample sizes limited definitive conclusions. Conclusions: Evidence for DNA methylation alterations in BPD is mixed, and current findings do not allow firm conclusions about their mechanisms or clinical relevance. Larger and longitudinal studies are required to clarify whether these epigenetic changes contribute meaningfully to BPD.