Causal relationship between methylation levels of CpG site in BDNF gene and risk of acute stress disorder:a two-sample Mendelian randomization analysis
10.11855/j.issn.0577-7402.1769.2025.0407
- VernacularTitle: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
- Author:
Yu-Qing TANG
1
;
Wei XIE
;
Hai-Hua BAI
;
Rui QIAO
Author Information
1. 包头医学院公共卫生学院,内蒙古包头 014000
- Keywords:
acute stress disorder;
brain-derived neurotrophic factor;
Mendelian randomization;
causal association;
stress
- From:
Medical Journal of Chinese People's Liberation Army
2025;50(8):925-934
- CountryChina
- Language:Chinese
-
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.
