Sun Yumeng, Lin Yuchen, Liang Nana, Xue Zhenpeng, Xu Jianchang, Lin Ling, Shen Yuan, Li Huiyan, Liu Jianbo, Lu Jianping
Department of Child Psychiatry of Shenzhen Kangning Hospital, Shenzhen Mental Health Center, Shenzhen Institute of Mental Health, Shenzhen, China.
The Brain Cognition and Brain Disease Institute, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China.
J Affect Disord. 2025 Feb 1;370:439-448. doi: 10.1016/j.jad.2024.10.029. Epub 2024 Oct 22.
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.
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.
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.
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.
新出现的证据表明，DNA甲基化在精神障碍的病理生理学中至关重要。本研究试图确定患有抑郁发作（DE）的青少年患者中DNA甲基化模式的失调情况，同时考虑各种亚型的影响，包括精神病性症状和童年创伤史。
该研究纳入了67例DE患者和30例健康对照（HC）受试者。重度抑郁发作（SDE）患者根据精神病性症状进行分组，如伴有与不伴有精神病性症状的SDE（病例分别为29例和21例）。儿童创伤问卷简版有助于评估所有患者的童年创伤情况。因此，所有患者被分为经历≥两种创伤类型的青少年DE患者与经历≤一种创伤类型的患者（病例分别为50例和17例）。对外周血进行全基因组甲基化分析，以确定三组比较中CpG位点的甲基化差异：DE组与HC组、伴有与不伴有精神病性症状的SDE患者、童年创伤类型为0 - 1种的DE患者与童年创伤类型≥两种的患者。
青少年DE患者表现出甲基化水平低于HC组的主要趋势，有259个高甲基化位点和3956个低甲基化位点。差异低甲基化位点涉及FKBP5、BDNF、NR3C1、GABRB3、SHANK1、SLC38A1、SLC6A18、CHRNB1、CTNNA2、CTTNBP2等相关基因。所有这些基因可能都参与了DE的发病机制。在伴有与不伴有精神病性症状的SDE亚组中可观察到显著的DNA甲基化差异（如DTNB、CNTN1、CTNNA2等基因），以及童年创伤类型为0 - 1种的DE患者与童年创伤类型≥两种的患者之间的差异（如VWA3B、SYT10、SDK2、CAMSAP3）。许多显著的甲基化位点与参与大脑发育的基因相关，突出了与DE及其亚型（如精神病性症状和童年创伤）相关的潜在病理生理机制。
我们的研究结果表明，DNA甲基化差异与DE的病理生理学以及精神病性症状和童年创伤史有关。这些基于血液的甲基化模式可能作为DE的生物标志物，并揭示这些亚型的潜在机制。
