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–ACE 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–sex interactions. Results. Significant rs1801260 × 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 × rs1801260 interaction in the corpus callosum, internal capsule and corona radiata. A GLZ model with separate slopes confirmed physical abuse × sex × 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–androgen modulation of clock genes, HPA axis, and myelination.
Adolescence and young adulthood are critical periods for the emergence of bipolar disorder (BD). Instability in sleep and rest-activity rhythms is associated with elevated risk for BD, yet little is known about the neural correlates of this vulnerability. White matter organization in fronto-limbic pathways, which support mood regulation and show sensitivity to sleep/rest-activity rhythm disruption, offers a promising avenue for investigation. Participants (16-24y;N = 112) recruited across a spectrum of mania vulnerability (MOODS-SRL) completed 14 days of actigraphy followed by a neuroimaging assessment. Diffusion MRI was used to derive Neurite Orientation Dispersion and Density Imaging, focusing on the Orientation Dispersion Index (ODI) of the cingulum bundle, uncinate fasciculus, and forceps minor. Clinician-rated symptoms of mania and depression were assessed at baseline and 6-months follow-up. We evaluated whether the links between actigraphy-derived sleep duration variability, sleep onset variability, and Circadian Function Index (CFI; index of circadian rhythm robustness) and white matter ODI were moderated by baseline mania vulnerability, and tested whether baseline ODI predicted 6-month mood symptoms. At higher levels of mania vulnerability, lower CFI (greater rest-activity instability) associated with higher ODI (greater white matter disorganization) in the cingulum bundle (β=-0.22;P = 0.029) and uncinate fasciculus (β = -0.22;P = 0.020). Moreover, higher uncinate fasciculus ODI predicted greater mania symptoms at 6-month follow-up and fully mediated the CFI-mania symptom association (β = -0.10;95 %CI[-0.14,-0.02]). Rest-activity instability may disrupt fronto-limbic white matter, increasing risk to mania in those at elevated vulnerability for BD. Stabilizing rest-activity rhythms in at-risk individuals may help preserve white matter integrity and mitigate BD risk.
João Paulo Lima Santos, Lara Labardini, Lauren Keller et al.· Psychiatry Research· 0 citations
INTRODUCTION
Depression is a highly heterogeneous disorder with a similarly heterogeneous neurobiological background. Understanding separate depressive phenotypes, driven by distinct aetiological pathways like early trauma and neurobiological contributors, can improve treatment. Furthermore, sex differences must be considered, as both the development and treatment of depression may be sex-specific. We aimed to investigate the sex-dependent association between polygenic risk for chronotypes, childhood traumas, and depression.
METHODS
In a discovery sample of 273,033 participants GWASs were ran and polygenic risk scores (PRS) were calculated in a target sample of 25,476 participants, separately for morning and evening chronotypes. Effects of chronotype-PRS in interaction with childhood adversities were analysed.
RESULTS
We identified 39 significant lead-SPNs (single nucleotide polymorphisms) and 44 genes associated with morning chronotype, and 69 significant lead-SNPs and 76 genes for evening chronotype. Heritability was comparable, at 12.1% for morning and 11.8% for evening chronotypes. No significant main effect of either chronotype-PRS was found on depressive symptom scores, however, in interaction with childhood traumas, morningness-PRS showed a significant effect on depressive symptom scores in women.
DISCUSSION
Our findings highlight important sex differences in the aetiological role of known risk factors for depression, such as chronotype or early trauma, and may have implications in the prevention of mood disorders in those genetically vulnerable and exposed to early risk factors.
D. Gyorik, Dora Torok, Gyorgy Bagdy et al.· Dialogues in Clinical Neuros...· 0 citations
Systematic assessment of mood and circadian rhythms may offer a more comprehensive framework for identifying clinically relevant chronobiological disruption in patients with multiple sclerosis.
G. Cinesi, S. Sperandei, Ludovica Quattrucci et al.· Chronobiology International· 0 citations
CircS is associated with SCD severity, while exploratory analyses suggest possible nonlinear associations between CircS score and selected plasma biomarkers and male participants showed a stronger association with SCD-domain scores.
Dan Liu, C. Cai, Jingjing Zhang et al.· Journal of Affective Disorde...· 0 citations
The findings reveal a complex, sex-dependent genetic interaction that selectively influences anhedonia and anxiety, which highlights the value of considering sex-stratified genetic backgrounds and symptom specificity to advance personalised precision medicine in psychiatry.
G. L. Odierna, C. Sharpley, V. Bitsika· Brain Science· 0 citations