解放军医学杂志2025，Vol.50Issue(8)：925-934,10.DOI:10.11855/j.issn.0577-7402.1769.2025.0407
BDNF基因CpG位点甲基化水平与急性应激障碍发生风险的因果关系:两样本孟德尔随机化分析
Causal relationship between methylation levels of CpG site in BDNF gene and risk of acute stress disorder:a two-sample Mendelian randomization analysis
摘要
Abstract
Objective To investigate the potential association between methylation levels of CpG locus of brain-derived neurotrophic factor(BDNF)gene and risk of acute stress disorder(ASD)[post-traumatic stress disorder(PTSD)or post-traumatic depression].Methods(1)30 specific pathogen-free(SPF)-grade male ICR mice were randomly divided into control group,24 h restraint stress(Res)group,and Res+5-Aza-2'deoxycytidine(Res+5-Aza-cdR)group,with 10 mice in each group.An ASD mouse model was established using 24h restraint stress.The body weight of the mice was recorded daily.At 24 h and 48 h after the successful establishment of the model,open field tests were conducted to evaluate locomotor activity level and anxiety-like behavior of the mice.Reverse transcription-polymerase chain reaction(RT-PCR)and Western blotting were used to detect BDNF mRNA and protein expression levels in the hippocampus of mice in each group.(2)Relevant genome-wide association study(GWAS)summary data were utilized for instrumental variable(IV)selection.A two-sample Mendelian randomization(TSMR)approach was applied to analyze the causal relationship between CpG site methylation of BDNF gene and ASD risk.The leave-one-out method was used to verify the results.Results(1)The results of body weight monitoring and the open field test showed that compared with control group,the body weight,the residence time in the central area,the total movement distance,and the activity times of mice in Res group were significantly decreased(P＜0.001).Compared with Res group,the body weight,the residence time in the central area,the total movement distance and activity times of mice in Res+5-Aza group were significantly increased(P＜0.00l).The results of RT-qPCR and Western blotting showed that compared with control group,the expression levels of BDNF mRNA and protein in the hippocampus of the mice in Res group were significantly decreased(P＜0.05).Compared with Res group,the expression level of BDNF mRNA and protein in Res+5-Aza group was significantly higher(P＜0.001).(2)TSMR analysis results showed that the cg10635145 site in BDNF gene(OR=0.862,95％CI 0.793-0.938,P=0.043)was negatively correlated with the risk of PTSD.The cg08362738 site(OR=0.975,95％CI 0.960-0.992,P=0.003)was negatively correlated with the risk of trauma-related depression,whereas the cg18117895 site(OR=1.008,95％CI 1.000-1.016,P=0.047)was positively correlated with the risk of trauma-related depression.The results of Leave-one-out test showed that the causal relationship between the single nucleotide polymorphism(SNP)of CpG site in BDNF gene and ASD was not affected by a strong Ⅳ.Conclusion The CpG loci cg1063145 and cg08362738 of BDNF gene maybe protective factors for ASD-related diseases,while cg18117895 maybe a riskfactor.关键词
急性应激障碍/脑源性神经营养因子/孟德尔随机化/因果关联/压力Key words
acute stress disorder/brain-derived neurotrophic factor/Mendelian randomization/causal association/stress分类
医药卫生引用本文复制引用
唐雨晴,谢伟,白海花,乔瑞..BDNF基因CpG位点甲基化水平与急性应激障碍发生风险的因果关系:两样本孟德尔随机化分析[J].解放军医学杂志,2025,50(8):925-934,10.基金项目
This work was supported by the National Natural Science Foundation of China(82071479,31860307),and the Baotou Medical College Innovation Team Development Program(bycxtd-12) 国家自然科学基金(82071479,31860307) （82071479,31860307）
包头医学院创新团队发展计划项目(bycxtd-12) （bycxtd-12）
