{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T14:13:00Z","timestamp":1785507180516,"version":"3.56.0"},"reference-count":89,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T00:00:00Z","timestamp":1785456000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Background. Bipolar disorder (BD) is characterized by circadian rhythm disruptions, contributing to mood instability and recurrence. These rhythms are regulated by clock genes in the suprachiasmatic nucleus, including the CLOCK 3111T\/C (rs1801260) polymorphism that has been linked to delayed sleep phase, insomnia, and altered circadian expression. Both circadian disruption and adverse childhood experiences (ACEs) correlate with white matter (WM) abnormalities. We hypothesized that rs1801260 moderates ACE effects on WM microstructure in BD. Methods. We enrolled 137 BD patients in depressive episodes. Participants underwent 3T MRI, rs1801260 genotyping and completed the Childhood Trauma Questionnaire. Moderation (PROCESS) tested genotype\u2013ACE interactions on whole-brain fractional anisotropy (FA), axial diffusivity (AD), mean diffusivity (MD), and radial diffusivity (RD) values; voxel-wise TBSS (FSL Randomize) localized effects, with sex-stratified and GLZ analyses for genotype\u2013sex interactions. Results. Significant rs1801260 \u00d7 ACE interactions emerged for FA and RD across physical abuse, physical neglect, and emotional neglect. Higher ACEs were associated with lower FA\/higher RD only in CLOCK rs1801260*C carriers, mainly females. TBSS showed physical abuse \u00d7 rs1801260 interaction in the corpus callosum, internal capsule and corona radiata. A GLZ model with separate slopes confirmed physical abuse \u00d7 sex \u00d7 rs1801260 interactions on FA\/RD, with effects specific to female CLOCK rs1801260*C carriers but genotype-independent in males. Conclusions. rs1801260 moderates the impact of early-life stress on WM integrity in BD, particularly in emotion-regulation tracts, with CLOCK rs1801260*C carriers showing greater vulnerability. Effects are genotype-specific in females but genotype-independent in males, possibly reflecting sex-dimorphic neurodevelopment driven by estrogen\u2013androgen modulation of clock genes, HPA axis, and myelination.<\/jats:p>","DOI":"10.3390\/genes17080912","type":"journal-article","created":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T13:23:20Z","timestamp":1785504200000},"page":"912","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["CLOCK 3111T\/C Polymorphism and Sex Moderate the Effect of Childhood Trauma on White Matter Microstructure in Bipolar Disorder"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-4923-4457","authenticated-orcid":false,"given":"Federica","family":"Nozza","sequence":"first","affiliation":[{"name":"Psychiatry & Clinical Psychobiology, IRCCS Ospedale San Raffaele, 20132 Milano, Italy"},{"name":"Faculty of Psychology, Vita-Salute San Raffaele University, 20132 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beatrice","family":"Bravi","sequence":"additional","affiliation":[{"name":"Psychiatry & Clinical Psychobiology, IRCCS Ospedale San Raffaele, 20132 Milano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lidia","family":"Fortaner-Uy\u00e0","sequence":"additional","affiliation":[{"name":"Psychiatry & Clinical Psychobiology, IRCCS Ospedale San Raffaele, 20132 Milano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessia","family":"Giovanelli","sequence":"additional","affiliation":[{"name":"Faculty of Psychology, Vita-Salute San Raffaele University, 20132 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Paolini","sequence":"additional","affiliation":[{"name":"Psychiatry & Clinical Psychobiology, IRCCS Ospedale San Raffaele, 20132 Milano, Italy"},{"name":"Faculty of Psychology, Vita-Salute San Raffaele University, 20132 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3324-1359","authenticated-orcid":false,"given":"Cristina","family":"Lorenzi","sequence":"additional","affiliation":[{"name":"Psychiatry & Clinical Psychobiology, IRCCS Ospedale San Raffaele, 20132 Milano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7059-8242","authenticated-orcid":false,"given":"Sara","family":"Spadini","sequence":"additional","affiliation":[{"name":"Psychiatry & Clinical Psychobiology, IRCCS Ospedale San Raffaele, 20132 Milano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-8265-6632","authenticated-orcid":false,"given":"Greta","family":"D\u2019Orsi","sequence":"additional","affiliation":[{"name":"Psychiatry & Clinical Psychobiology, IRCCS Ospedale San Raffaele, 20132 Milano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina","family":"Colombo","sequence":"additional","affiliation":[{"name":"Psychiatry & Clinical Psychobiology, IRCCS Ospedale San Raffaele, 20132 Milano, Italy"},{"name":"Faculty of Psychology, Vita-Salute San Raffaele University, 20132 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9594-0246","authenticated-orcid":false,"given":"Sara","family":"Poletti","sequence":"additional","affiliation":[{"name":"Psychiatry & Clinical Psychobiology, IRCCS Ospedale San Raffaele, 20132 Milano, Italy"},{"name":"Faculty of Psychology, Vita-Salute San Raffaele University, 20132 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4949-856X","authenticated-orcid":false,"given":"Francesco","family":"Benedetti","sequence":"additional","affiliation":[{"name":"Psychiatry & Clinical Psychobiology, IRCCS Ospedale San Raffaele, 20132 Milano, Italy"},{"name":"Faculty of Psychology, Vita-Salute San Raffaele University, 20132 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,31]]},"reference":[{"key":"ref_1","first-page":"S80","article-title":"Bipolar disorder: Disease burden","volume":"11","author":"Sajatovic","year":"2005","journal-title":"Am. 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