Methylome-wide association study of adolescent depressive episode with psychotic symptoms and childhood trauma

BACKGROUND: Emerging evidence suggests that DNA methylation is crucial in the mental disorder pathophysiology. The current study attempted to identify the dysregulation of DNA methylation patterns in adolescent patients suffering from depressive episodes (DE) while considering the impact of various subtypes, including psychotic symptoms and a history of childhood trauma. METHODS: The study included 67 patients with DE and 30 healthy controls (HCs) subjects. Severe depressive episode (SDE) patients were grouped according to psychotic symptoms, such as SDE with vs. SDE without psychotic symptoms (cases 29 vs. 21). The Childhood Trauma Questionnaire-Short Form helped assess childhood trauma among all patients. Thus, all the patients were divided into adolescent DE experiencing ≥ two trauma types vs. experiencing ≤ one trauma type (cases, 50 vs. 17). Methylome-wide analysis was conducted on peripheral blood to identify methylation differences in CpG sites for three comparisons: DE vs. HCs, SDE patients with vs. without psychotic symptoms, and DE patients having 0-1 type of childhood trauma vs. those having ≥two types of childhood trauma. RESULTS: Adolescent DE patients demonstrated a predominant trend of lower methylation levels than HCs, with 259 hypermethylated and 3956 hypomethylated sites. Differentially hypomethylated sites involve related genes such as FKBP5, BDNF, NR3C1, GABRB3, SHANK1, SLC38A1, SLC6A18, CHRNB1, CTNNA2, CTTNBP2, etc. All these genes could be involved in DE pathogenesis. Significant DNA methylation differences could be observed in SDE subgroups with and without psychotic symptoms (e.g., genes like DTNB, CNTN1, CTNNA2), along with those DE patients having 0-1 type of childhood trauma compared to those with ≥2 types (e.g., VWA3B, SYT10, SDK2, CAMSAP3). Many significant methylated sites were associated with genes involved in brain development, highlighting the potential pathophysiological mechanisms linked with DE and its subtypes, such as psychotic symptoms and childhood trauma. CONCLUSION: Our findings suggest that differential DNA methylation is associated with the pathophysiology of DE, as well as the presence of psychotic symptoms and a history of childhood trauma. These blood-based methylation patterns may serve as biomarkers for DE and shed light on underlying mechanisms across these subtypes.