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DNA methylation, a key epigenetic mechanism, is crucial in understanding depressive symptoms development. The serotonin transporter gene (<jats:italic>5-HTT<\/jats:italic>) and its polymorphisms, like <jats:italic>5-HTTLPR<\/jats:italic>, 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) <jats:italic>5-HTT<\/jats:italic> promoter methylation levels between depressed and non-depressed conditions and (2) the association between <jats:italic>5-HTT<\/jats:italic> 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 \u2013 127 effects) indicated no significant effect (Hedges\u2019g\u2009=\u20090.06) with moderate within- and low between-study heterogeneity. The depression severity analysis (14 studies - 2296 subjects - 116 effects) revealed a null effect size (Fisher\u2019s Z\u2009=\u20090.05), 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 <jats:italic>5-HTT<\/jats:italic> promoter methylation and depressive symptoms. Furthermore, it offers well-considered recommendations for future research endeavors and delineates guidelines for reporting methylation research.<\/jats:p>","DOI":"10.1038\/s41398-025-03356-w","type":"journal-article","created":{"date-parts":[[2025,5,3]],"date-time":"2025-05-03T22:10:15Z","timestamp":1746310215000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Exploring the association between serotonin transporter promoter region methylation levels and depressive symptoms: a systematic review and multi-level meta-analysis"],"prefix":"10.1038","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4240-2588","authenticated-orcid":false,"given":"F.","family":"Javelle","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G.","family":"Dao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M.","family":"Ringleb","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"W.","family":"Pulverer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"W.","family":"Bloch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,5,3]]},"reference":[{"key":"3356_CR1","unstructured":"Global Health Data. 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