Javelle F, Dao G, Ringleb M, Pulverer W, Bloch W
NeuroPsychoImmunology research unit, Department for Molecular and Cellular Sports Medicine, Institute for Cardiovascular Research and Sports Medicine, German Sport University Cologne, Cologne, Germany.
University of Cologne, Cologne, Germany.
Transl Psychiatry. 2025 May 3;15(1):161. doi: 10.1038/s41398-025-03356-w.
Depressive disorders result from complex interactions among genetic, epigenetic, and environmental factors. DNA methylation, a key epigenetic mechanism, is crucial in understanding depressive symptoms development. The serotonin transporter gene (5-HTT) and its polymorphisms, like 5-HTTLPR, have been extensively studied in relation to depression, yet conflicting findings regarding the association between 5-HTT promoter methylation and depressive symptoms persist, largely due to methodological differences. Thus, this systematic review and meta-analysis aims to assess (1) 5-HTT promoter methylation levels between depressed and non-depressed conditions and (2) the association between 5-HTT methylation and depressive symptoms severity. We searched PubMed, Google Scholar, and Web of Science from inception to January 15th, 2025 (PROSPERO: CRD42023355414) and performed two independent multi-level meta-analyses to answer our aims. Twenty-four trials were included in the systematic review. All reported effects carried potential for bias. The meta-analysis for depression occurrence (12 studies - 2028 subjects - 127 effects) indicated no significant effect (Hedges'g = 0.06) with moderate within- and low between-study heterogeneity. The depression severity analysis (14 studies - 2296 subjects - 116 effects) revealed a null effect size (Fisher's Z = 0.05), with no within- and moderate between-study heterogeneity. Asymmetry was detected for both meta-analyses. Moderator analyses demonstrated no significant effects of depression severity, methylation techniques, single-CpG sites, cell types assessed, age, and female percentage. This comprehensive review provides insights into the intricate interplay between 5-HTT promoter methylation and depressive symptoms. Furthermore, it offers well-considered recommendations for future research endeavors and delineates guidelines for reporting methylation research.
抑郁症是由遗传、表观遗传和环境因素之间的复杂相互作用引起的。DNA甲基化作为一种关键的表观遗传机制，对于理解抑郁症状的发展至关重要。血清素转运体基因（5-HTT）及其多态性，如5-HTTLPR，已针对抑郁症进行了广泛研究，但关于5-HTT启动子甲基化与抑郁症状之间关联的研究结果仍存在冲突，这在很大程度上是由于方法学上的差异。因此，本系统评价和荟萃分析旨在评估：（1）抑郁状态与非抑郁状态之间的5-HTT启动子甲基化水平；（2）5-HTT甲基化与抑郁症状严重程度之间的关联。我们检索了从数据库建立至2025年1月15日的PubMed、谷歌学术和科学网（PROSPERO：CRD42023355414），并进行了两项独立的多层次荟萃分析以实现我们的研究目标。系统评价纳入了24项试验。所有报告的效应都存在偏倚可能性。抑郁症发生情况的荟萃分析（12项研究 - 2028名受试者 - 127个效应）表明无显著效应（Hedges'g = 0.06），研究内异质性为中度，研究间异质性为低度。抑郁严重程度分析（14项研究 - 2296名受试者 - 116个效应）显示效应量为零（Fisher's Z = 0.05），研究内无异质性，研究间异质性为中度。两项荟萃分析均检测到不对称性。调节因素分析表明，抑郁严重程度、甲基化技术、单个CpG位点、评估的细胞类型、年龄和女性百分比均无显著效应。这一全面综述深入探讨了5-HTT启动子甲基化与抑郁症状之间的复杂相互作用。此外，它为未来的研究工作提供了深思熟虑的建议，并阐述了甲基化研究报告的指南。
