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

Polygenic Risk for Major Depression: Diagnostic Specificity and Developmental Trajectories in an Admixed Youth Cohort.

BACKGROUND Major Depressive Disorder (MDD) is heritable and polygenic, yet the relative diagnostic specificity, developmental impact, and cross-ancestry generalizability of MDD polygenic risk scores (MDD-PRS) remain unclear. METHODS In two sites of the Brazilian High-Risk Cohort (N=2,163; ages 6-23; 45.6% female), we used a discovery-replication design to test associations between MDD-PRS and (i) lifetime DSM-IV diagnoses; (ii) longitudinal depressive-symptom trajectories from latent growth-curve models; and (iii) late-adolescent/young-adult depressive symptoms and nonsuicidal self-injury (NSSI). Analyses used weighted ordinary least squares and quantile regression, adjusting for age, sex, socioeconomic status, genetic principal components, and psychiatric comorbidity. RESULTS MDD-PRS showed relative specificity for MDD in both sites, explaining approximately 2.6-3.6% of liability-scale variance; no other diagnostic category survived false-discovery-rate correction. Longitudinally, higher MDD-PRS predicted higher initial level (β=0.10-0.18; p<0.001 in both sites), faster rate of increase (β=0.07-0.10; p=0.004 and p<0.001), and higher time-averaged level (β=0.13-0.20; p<0.001 in both sites) of depressive symptoms, with effects strengthening at higher quantiles. Cross-sectionally, MDD-PRS were associated with more depressive symptoms (β=0.15-0.17; p<0.001 in both sites). For NSSI, a main-effect association was observed (β=0.09; p<0.001), but it remained significant only in a post-hoc MDD-PRS×lifetime-MDD interaction among individuals with MDD (β=0.24; p=0.014). CONCLUSIONS In this deeply phenotyped, admixed cohort, MDD-PRS showed relative diagnostic specificity and marked a more severe developmental course of depression, with NSSI associations contingent on MDD diagnosis, supporting the relative specificity, developmental utility, and cross-ancestry relevance of MDD-PRS.

Prolonged Childhood and Adolescent Loneliness in First-Episode Psychosis: Synergistic Polygenic Effects and Functional Outcomes.

Integrating biological pathway polygenic scores and trauma in psychosis: findings from the EU-GEI study

Psychotic disorders are complex, multifactorial conditions influenced by both genetic liability and early environmental adversity. Polygenic risk scores (PRSs) derived from genome-wide association studies have shown utility in capturing genetic predisposition, but their biological interpretability remains limited. In this study, we evaluated whether biologically informed pathway-specific polygenic scores (pPGSs) for psychosis, restricted to neurotransmitter-related pathways, could help clarify gene-environment interplay. Using data from 1 192 individuals in the EU-GEI multi-site case-control study, we constructed pPGSs for dopamine, glutamate, GABA, and serotonin systems. We investigated associations between pPGSs and childhood trauma (rGE), their interactions on psychosis risk (GxE), and the influence of the genome-wide psychosis PRS on these relationships. Serotonin, dopamine, and glutamate pPGSs were positively associated with a composite trauma exposure (i.e., abuse and neglect), suggesting shared genetic factors contributing to both psychosis liability and early adversity. Significant negative GxE effects were observed for both dopamine and serotonin pPGSs, indicating that higher trauma exposure diminished the relative influence of genetic liability on psychosis risk. Adjustment for the genome-wide psychosis PRS attenuated most effects, but serotonergic and dopaminergic associations remained robust, supporting pathway-specific contributions beyond general polygenic risk. These findings provide proof-of-concept for the utility of pPGSs in psychiatric research, suggesting both genetic contributions to trauma exposure and GxE effects on psychosis risk. Further research incorporating epigenetic data and longitudinal designs may enhance mechanistic insight and translational potential.

Bidirectional Mendelian randomization of childhood maltreatment and sleep-related phenotypes.

Background: Childhood maltreatment (CM) is associated with sleep disturbance, but observational findings may be affected by confounding, shared familial liability, and reverse-direction explanations. We conducted bidirectional two-sample Mendelian randomization (MR) to examine genetic evidence linking composite CM liability with six sleep-related phenotypes.Methods: Genetic instruments for CM were obtained from a large European-ancestry multi-cohort GWAS meta-analysis. CM was defined as a composite phenotype encompassing multiple abuse and neglect subtypes and ascertainment modes. Summary statistics for chronotype, daytime sleepiness (DS), insomnia symptoms, sleep apnea (SA), daytime napping (DN), and sleep duration (SD) were derived from large European-ancestry GWASs. Inverse-variance weighted MR was the primary method, with weighted median and MR-Egger sensitivity analyses. Benjamini-Hochberg correction was applied and reported as P(BH).Results: In forward MR, genetically proxied CM was associated with higher DS (OR = 1.04, 95% CI 1.01-1.07; P(BH) = 0.030), insomnia symptoms (OR = 1.08, 95% CI 1.01-1.15; P(BH) = 0.030), and DN (β = 0.07, 95% CI 0.03-0.09; P(BH) = 0.002). Little evidence was observed for chronotype, SA, or SD. In exploratory reverse-direction MR, genetic liability to DN (β = 0.16, 95% CI 0.05-0.27; P(BH) = 0.012) and insomnia symptoms (β = 0.21, 95% CI 0.07-0.35; P(BH) = 0.012) was associated with CM liability.Conclusions: This study provides suggestive genetic evidence linking composite CM liability with selected sleep-related phenotypes, particularly self-reported DS, insomnia symptoms, and DN. Reverse-direction findings may reflect shared genetic liability, gene-environment correlation, reporting-related mechanisms, or broader familial pathways rather than temporal effects of adult sleep traits on CM. Given modest effects and uneven sensitivity support, findings should be interpreted cautiously.

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

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.

Clinical, sociodemographic, and genetic predictors of depressive episode duration in the UK Biobank

Background: The course of major depressive disorder is heterogeneous, with UK Biobank (UKB) participants reporting episode durations ranging from <1 month to >24 months. Here, we identify predictors of episode duration, characterise its genetic architecture, and examine links to treatment seeking and response. Methods: In UKB participants meeting criteria for major depressive disorder, we examined clinical, sociodemographic, and genetic predictors of short (0-3 months) and long (>24 months) episode duration, fitted in predictor-specific, domain-level, and combined models. We also conducted genome-wide association studies in European-ancestry participants (n = 40,858) and estimated common-variant heritability. Results: Clinical features were most informative: higher childhood trauma scores, a stressful trigger, and recurrence showed the most consistent associations with short and long durations across models (ORcombined: short = 0.75-0.95; long = 1.13-1.45; all p[≤]0.02). Higher neuroticism scores were also associated with both durations (ORcombined: short = 0.977; long = 1.053; p<0.001). Polygenic risk for depression was associated with episode duration, though its independent contribution was modest. Long episodes were more predictable than short in validation analyses (AUC = 0.705 vs 0.601) and were associated with greater treatment engagement but lower perceived benefit; SNP-based heritability was nominally significant. Conclusions: Clinical features captured most of the predictable variance in episode duration, with the same predictors largely operating in opposite directions for short and long episodes, consistent with a continuum of chronicity. Those at risk for long episodes emerge as a priority for early identification and intervention.