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This study determined whether methylation levels moderate the association between biopsychosocial factors and depression. Using cross-sectional data from the Taiwan Biobank 2016\u20132017, the study examined the effects of biopsychosocial factors and DNA methylation on depression. The sample consisted of 96 participants aged 30 to 68 years. Depression and biopsychosocial factors were evaluated using self-reported questionnaires. Biopsychosocial factors included biological factors (age, sex, physical illness, body mass index [BMI]), psychological factors (alcohol experience, smoking experience, and exercise habit), and social factors (education, marriage, and dependency). To obtain methylated gene data, the Taiwan Biobank 2016\u20132017, 65 biological risk genes, and the GSE113725 dataset were intersected, revealing 5 genes and 14 CpG sites potentially associated with depression (\n                    <jats:italic>IL2RB-cg02238178<\/jats:italic>\n                    ,\n                    <jats:italic>IL2RB-cg11558856<\/jats:italic>\n                    ,\n                    <jats:italic>IL15RA-cg03108606<\/jats:italic>\n                    ,\n                    <jats:italic>IL15RA-cg07796897<\/jats:italic>\n                    ,\n                    <jats:italic>IL15RA-cg08676905<\/jats:italic>\n                    ,\n                    <jats:italic>IL6R-cg25853020<\/jats:italic>\n                    ,\n                    <jats:italic>IL6R-cg09257526<\/jats:italic>\n                    ,\n                    <jats:italic>IL6R-cg04715245<\/jats:italic>\n                    ,\n                    <jats:italic>FTL-cg04385818<\/jats:italic>\n                    ,\n                    <jats:italic>FTL-cg03039974<\/jats:italic>\n                    ,\n                    <jats:italic>ZNF614-cg09503196<\/jats:italic>\n                    ,\n                    <jats:italic>ZNF614-cg25776555<\/jats:italic>\n                    ,\n                    <jats:italic>ZNF614-cg03293882<\/jats:italic>\n                    , and\n                    <jats:italic>ZNF614-cg15684917<\/jats:italic>\n                    ). The results indicated that BMI was negatively associated with depression risk (adjusted odds ratio [aOR]\u2009=\u20090.320, 95% confidence interval [CI] [0.117\u20130.876]), whereas the methylation of\n                    <jats:italic>IL6R_cg09257526<\/jats:italic>\n                    increased the risk of depression (aOR\u2009=\u20092.535, 95% CI [1.006\u20136.391]) and significantly moderated the association between BMI and depression (aOR\u2009=\u20094.687, 95% CI [1.185\u201318.542]). BMI plays a crucial role in biological factors and together with DNA methylation of the\n                    <jats:italic>IL6R_cg09257526<\/jats:italic>\n                    gene contributes to the occurrence of depression in the Taiwanese population.\n                  <\/jats:p>","DOI":"10.1038\/s41398-025-03596-w","type":"journal-article","created":{"date-parts":[[2025,11,22]],"date-time":"2025-11-22T09:33:07Z","timestamp":1763803987000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["DNA methylation of the IL6R gene moderates the association between biopsychosocial factors and depression"],"prefix":"10.1038","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2434-4759","authenticated-orcid":false,"given":"Reni Merta","family":"Kusuma","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mohammad Hendra Setia","family":"Lesmana","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vivi Leona","family":"Amelia","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Muhamad","family":"Ansar","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9965-778X","authenticated-orcid":false,"given":"Bayu Satria","family":"Wiratama","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Muhammad Solihuddin","family":"Muhtar","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0517-5913","authenticated-orcid":false,"given":"Min-Huey","family":"Chung","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2025,11,22]]},"reference":[{"key":"3596_CR1","doi-asserted-by":"publisher","first-page":"480","DOI":"10.2174\/1570159X1304150831123535","volume":"13","author":"R Cui","year":"2015","unstructured":"Cui R. 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