CLOCK 3111T/C Polymorphism and Sex Moderate the Effect of Childhood Trauma on White Matter Microstructure in Bipolar Disorder

White matter microstructure mediates the link between rest-activity rhythm instability and mania symptoms in individuals at risk for bipolar disorder.

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.

Genetic liability for morning chronotype interacts with childhood trauma to predict depressive symptoms in women.

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.

Circadian rhythm disruption and multiple sclerosis: The role of affective symptoms and temperamental traits.

Sleep and circadian rhythm disturbances are common clinical features in people with multiple sclerosis (PwMS) and related demyelinating conditions. Affective symptoms may shape vulnerability to circadian dysregulation. This pilot cross-sectional study examined how affective symptoms and underlying temperamental dispositions relate to circadian rhythm instability in a population of newly diagnosed PwMS and related demyelinating conditions, defined as patients evaluated within 30 days after discharge from the index hospitalization during which the diagnosis was established. Measures included Beck Depression Inventory-II (BDI-II), State-Trait Anxiety Inventory (STAI-Y), Biological Rhythm Interview for Assessment in Neuropsychiatry (BRIAN), Morningness-Eveningness Questionnaire, and brief Temperament Evaluation of Pisa, Memphis, and San Diego. Pearson correlations explored associations among circadian, affective, and temperament dimensions. A multiple linear regression tested independent psychopathological variables associated with BRIAN total scores. In our sample (n = 77; mean age 33 y; 71% women; 81.8% relapsing-remitting MS), clinically relevant depressive symptoms were present in 22%, and state/trait anxiety in 46% and 41% PwMS, respectively. Circadian dysregulation (BRIAN ≥ 40) showed a prevalence of 13.7%. BRIAN scores correlated with BDI-II (r = .68), STAI-Y1/Y2 (r = .55-.60), and depressive/cyclothymic/anxious/irritable temperaments (r = .37-.42). In the regression model (adjusted R2 = .521), depressive symptom severity displayed the strongest association with circadian disruption (β = .562, p < 0.001), with a smaller contribution of depressive temperament (β =-.385, p = 0.017). Both current affective symptoms and underlying temperamental traits may contribute to circadian rhythm instability in MS. Systematic assessment of mood and circadian rhythms may offer a more comprehensive framework for identifying clinically relevant chronobiological disruption in these patients.

Circadian syndrome, subjective cognitive decline, and plasma biomarkers: Sex-specific patterns and non-linear biomarkers associations.

BACKGROUND Established evidence linking circadian syndrome (CircS) to cognitive impairment. However, the association with subjective cognitive decline (SCD) and its sex-specific patterns remains unclear. METHODS This cross-sectional study included 2008 cognitively normal adults from the Hubei Memory and Aging Cohort Study (HMACS). CircS was evaluated by metabolism, sleep, and depression. SCD was assessed based on the SCD-I framework. Regression, restricted cubic spline, subgroup analyses, and indirect-effect analysis were performed. RESULTS CircS was associated with various SCD outcomes, with a dose-response relationship. CircS was dose-responsively linked to GFAP and nonlinearly to Aβ42/40 (Pₙₒₙₗᵢₙₑₐᵣ = 0.029) and NfL (Pₙₒₙₗᵢₙₑₐᵣ = 0.030). Subgroup analysis revealed that CircS was associated with higher SCD-domain in males (β = 0.32, 95% CI: 0.14-0.49; P for interaction = 0.003), and lower GFAP levels in females (β = -0.25, 95% CI: -0.38 to -0.11; P for interaction = 0.021). Indirect-effect models did not show evidence of the inflammatory markers examined statistically accounted for the observed association between CircS and SCD. CONCLUSIONS CircS is associated with SCD severity, while exploratory analyses suggest possible nonlinear associations between CircS score and selected plasma biomarkers. Male participants showed a stronger association with SCD-domain scores. The clinical implications of these findings require validation in longitudinal studies.

Anxiety and Depression Traits Are Moderated by a Sex-Dependent Genetic Interaction Between 5-HTTLPR and BDNF

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.

CLOCK rs1801260 and MTNR1B rs10830963 Polymorphisms Modulate the Association between Cholesterol Levels and Circadian Rhythms in Arctic Residents