背景:电惊厥治疗(ECT)有益于治疗抵抗抑郁症(TRD)的患者,但潜在的生物过程尚不清楚。我们在32例接受ECT的TRD患者中进行了一项表观基因组关联研究,以描述ECT相关的甲基化变化。在基线(T0)和结束后1个月(T1)使用蒙哥马利-奥斯贝格抑郁量表评估疾病严重程度和ECT结局。用IlluminaInfinium甲基化EPICBeadChip阵列在T0和T1进行甲基化分析。
结果:纵向T0-T1分析显示3个差异甲基化探针(DMPs),标称p值≤10-5,其中2个在CYB5B和PVRL4基因中注释。包括协变量,我们发现了4种症状变异的DMPs,在FAM20C中注释,EPB41、OTUB1和ADARB1,以及3个响应状态的DMP,在IQCE和FAM20C中注释了2个。区域分析显示54个差异甲基化区域(DMRs),标称p值面积≤0.05,其中9个显示调整后的p值面积≤0.10,以MCF2L注释,SLC25A24,RUNX3,MIR637,FOXK2,FAM180B,POU6F1、ALS2CL和CCRL2。考虑协变量,我们发现21个DMRs用于症状变化,26个DMRs用于反应(标称p值面积≤0.05),4表示响应的调整后p值面积≤0.10,注解在SNORD34、NLRP6、GALNT2和SFT2D3。错误发现率校正后,没有一个仍然很重要。值得注意的是,ADARB1变体与精神疾病患者的自杀企图有关,SLC25A24与行为障碍有关。在与炎症/免疫过程相关的基因中注释了几种DMPs和DMRs。对女性(n=22)的纵向分析显示,症状变化和反应状态具有统计学意义的DMRs(调整后的p值面积≤0.05)和趋势显着的DMRs(调整后的p值面积≤0.07)。在与精神疾病相关的基因中注释(ZFP57,POLD4,TRIM10,GAS7,ADORA2A,TOLLIP),创伤暴露(RIPOR2)和炎症/免疫反应(LAT,DLX4,POLD4,FAM30A,H19).对女性的通路分析揭示了转录活性的富集,生长因子,DNA维持,免疫途径包括IRF7和IRF2。
结论:虽然在整个队列中没有发现显著的结果,这项研究提供了对ECT相关甲基化变化的见解,强调与ECT结局相关的DMP和DMRs。对女性的分析显示,与精神疾病和炎症/免疫过程相关的DMRs和途径显着。
BACKGROUND: Electroconvulsive therapy (ECT) benefits patients with treatment-resistant depression (
TRD), but the underlying biological processes are unclear. We conducted an epigenome-wide association study in 32
TRD patients undergoing ECT to depict ECT-associated methylation changes. Illness severity and ECT outcomes were assessed with the Montgomery-Åsberg Depression Rating Scale at baseline (T0) and 1 month after its end (T1). Methylation was profiled at T0 and T1 with the Illumina Infinium Methylation EPIC BeadChip array.
RESULTS: Longitudinal T0-T1 analyses showed 3 differentially methylated probes (DMPs) with nominal p values ≤ 10-5, with 2 annotated in the genes CYB5B and PVRL4. Including covariates, we found 4 DMPs for symptoms variation, annotated in FAM20C, EPB41, OTUB1 and ADARB1, and 3 DMPs for response status, with 2 annotated in IQCE and FAM20C. Regional analysis revealed 54 differentially methylated regions (DMRs) with nominal p value area ≤ 0.05, with 9 presenting adjusted p-value area ≤ 0.10, annotated in MCF2L, SLC25A24, RUNX3, MIR637, FOXK2, FAM180B, POU6F1, ALS2CL and CCRL2. Considering covariates, we found 21 DMRs for symptoms variation and 26 DMRs for response (nominal p value area ≤ 0.05), with 4 presenting adjusted p-value area ≤ 0.10 for response, annotated in SNORD34, NLRP6, GALNT2 and SFT2D3. None remained significant after false discovery rate correction. Notably, ADARB1 variants are associated with suicide attempt in patients with psychiatric disorders, and SLC25A24 relates to conduct disorder. Several DMPs and DMRs are annotated in genes associated with inflammatory/immune processes. Longitudinal analyses on females (n = 22) revealed statistically significant DMRs (adjusted p value area ≤ 0.05) and trend-significant DMRs (adjusted p value area ≤ 0.07) for symptoms variation and response status, annotated in genes related to psychiatric disorders (ZFP57, POLD4, TRIM10, GAS7, ADORA2A, TOLLIP), trauma exposure (RIPOR2) and inflammatory/immune responses (LAT, DLX4, POLD4, FAM30A, H19). Pathway analysis on females revealed enrichment for transcriptional activity, growth factors, DNA maintenance, and immune pathways including IRF7 and IRF2.
CONCLUSIONS: Although no significant results were found for the whole cohort, the study provides insights into ECT-associated methylation changes, highlighting DMPs and DMRs related to ECT outcomes. Analyses on females revealed significant DMRs and pathways related to psychiatric disorders and inflammatory/immune processes.