Large biobanks offer unprecedented data for psychiatric genomic research, but concerns exist about representativeness and generalizability. This study examined depression prevalence and polygenic risk score (PRS) associations in the All of Us data to assess potential impacts of nonrepresentative sampling.

Depression prevalence and correlates were analyzed in two subsamples: those with self-reported personal medical history (PMH) data (N = 185,232 overall; N = 114,739 with genetic data) and those with electronic health record (EHR) data (N = 287,015 overall; N = 206,175 with genetic data). PRS weights were estimated across ancestry groups. Associations of PRS with depression were examined by state and ancestry.

Depression prevalence varied across states in both PMH (16.7–35.9%) and EHR (0.2–45.8%) data. Concordance between PMH and EHR diagnoses was low (kappa: 0.29, 95% CI: 0.30–0.30). Overall, one standard deviation increase in depression PRS was associated with lifetime depression based on PMH (odds ratio [OR] = 1.05, 95% confidence interval [CI]: 1.04–1.07) and EHR (OR = 1.05, 95% CI: 1.04–1.07). Results were generally consistent by ancestry, with the strongest signal for European ancestry (PMH: OR = 1.10, 95% CI: 1.08–1.12; EHR: OR = 1.07, 95% CI: 1.05–1.10). Associations between PRS and lifetime depression were largely consistent and significant associations varied minimally (ORs = 1.06–1.45) by state of residence in both subsamples.

Recorded depression prevalence by state in All of Us demonstrates a wide range, likely reflecting recruitment differences, EHR data completeness, and true geographic variation; yet PRS associations remained relatively stable. As studies like All of Us expand, accounting for sample composition and measurement approaches will be crucial for generating actionable findings.

Social connections might be protective against depressive and anxious symptoms and dementia in later life. The extent to which social connections are heritable versus modifiable in older age remains unknown.

We aimed to investigate the heritability of social connections and their influence on mental and cognitive health over time among older adults in a longitudinal cohort.

We analysed data from the Older Australian Twins Study (333 monozygotic, 266 dizygotic twins; 65+ years) at three time-points over 6 years. We examined the factor structure and heritability of baseline social connections and their associations with mental and cognitive health longitudinally.

We found three weakly heritable social connections factors: (a) interacting with friends/neighbours/community (h2 = 0.09, 95% CI: 0.00, 0.44); (b) family interactions/childcare (h2 = 0.13, 95% CI: 0.00, 0.43); (c) involvement in religious groups/caregiving (h2 = 0.00, 95% CI: 0.00, 0.19). Strong genetic correlations were observed between depressive symptoms and factors a (r = −0.96) and b (r = −0.60). More frequent baseline interactions with friends/neighbours/community were associated with fewer depressive symptoms cross-sectionally (B = −0.14, p = .004) and longitudinally (B = −0.09, p = 0.006), but the associations between social connections and cognitive health were not significant.

Social connections were weakly heritable, suggesting large environmental determination. Connections with friends/neighbours/community were associated with better mental health cross-sectionally and over time.

Major depressive disorder (MDD) exhibits significant heterogeneity in treatment responses, necessitating multiple pharmacological trials to achieve therapeutic success. Pharmacogenetic (PGx) testing has emerged as a promising tool to personalize antidepressant (AD) treatments, though its clinical utility remains controversial.

This study assessed the efficacy of PGx-guided treatment in improving clinical outcomes among 287 MDD patients within the PANDORA trial, a prospective randomized, participant- and rater-blinded, controlled trial conducted in Italy. A total of 268 adults with moderate-to-severe MDD were randomized into Treated as Usual (TAU) or Treated with Genetic Test Guide (TGTG). Patients were assessed using the Hamilton Depression Rating Scale (HAM-D17), Beck Depression Inventory II (BDI-II), Beck Anxiety Inventory, MINI-ICF-APP for psychosocial functioning, and the UKU Side Effects Rating Scale, at baseline and at 4, 8, and 12 weeks.

Both groups demonstrated significant symptom improvement over the 12-week period. No significant differences were observed between the groups in terms of response and remission rates, measured by HAM-D17 and BDI-II, at weeks 8 and 12. Notably, in the BDI-II symptom cluster analysis, significant differences were found only in neurovegetative symptoms, with TGTG patients showing greater improvement at the 4-week and 8-week follow-up visits. Among patients with severe baseline symptoms, those in the TGTG group exhibited greater symptom reduction and higher response rates at week 8.

These findings suggest that while PGx testing did not significantly improve overall treatment efficacy in MDD compared to TAU, it may offer benefits in managing patients with severe symptoms and specific symptom domains.

Neuroticism, a personality trait linked to both cardiovascular and psychiatric disorders, has been associated with cognitive decline and increased dementia risk, though the underlying neural mechanisms remain unclear. Mapping its relationship with brain structure could provide valuable insights into neural pathways and targets for early intervention.

We examined brain-wide associations between neuroticism and structural neuroimaging metrics derived from T1-, T2-weighted, and diffusion MRI in 36,901 dementia-free UK Biobank participants. Bonferroni-significant associations underwent bidirectional two-sample Mendelian randomization to evaluate the evidence for a causal relationship. Given that neuroticism is generally stable across adulthood and challenging to modify, we assessed whether these associations were mediated by health conditions (depression, anxiety, hypertension, ischemic heart disease [IHD], and diabetes) that are both consequences of neuroticism and known risk factors for dementia, and also modifiable through widely available and efficacious therapeutic interventions.

Higher neuroticism was found to be associated with reduced grey matter volumes in the frontal and limbic regions, as well as widespread differences in white matter microstructure, particularly in thalamic radiations. Genetic analyses supported a potential causal effect of neuroticism on increased diffusivity in thalamic radiations. Hypertension mediated the associations between neuroticism and both grey and white matter measures, while depression and anxiety primarily mediated associations with white matter microstructure. Contributions from IHD and diabetes were minimal.

Neuroticism is linked to widespread structural brain differences that contribute to poorer brain health, and targeting vascular and mental health may help mitigate its impact.

Childhood maltreatment is a robust predictor of aggression. Research indicates that both maltreatment experiences and aggression are moderately heritable. It has been hypothesized that gene–environment correlation may be at play, whereby genetic predispositions to aggression in parents and children may be confounded with family environments conducive to its expression. Building on this framework, we tested whether maltreatment mediates the association between a polygenic score for aggression (PGSAGG) and school-age aggression, and whether this varied for reactive and proactive aggression.

The sample comprised 721 participants (44.9% males; 99.0% White) with prospective assessments of maltreatment from 5 months to 12 years (10 assessments;1998–2010), and teachers-reported aggression from ages 6 to 13 (6 assessments; 2004–2011). The PGSAGG was derived using a Bayesian estimation method (PRS-CS).

PGSAGG was associated with most aggression measures across specific ages and trajectories. Maltreatment experiences partially mediated the association between PGSAGG and the Childhood-Limited trajectory of reactive – but not proactive – aggression.

Children with higher genetic propensities for aggression were more likely to experience maltreatment, which partly explained the association between PGSAGG and a Childhood-Limited trajectory of reactive aggression during elementary school. This finding reinforces the possibility of confounding influences between genetic liability for aggression and maltreatment experiences.

Although global knowledge on paediatric cardiomyopathies has advanced, prospective cohort studies from Brazil, particularly those integrating clinical and genetic data, remain limited.

To describe the clinical and genetic characteristics of paediatric cardiomyopathy patients and identify mortality predictors in a metropolitan region of Brazil.

Prospective observational study of paediatric patients with cardiomyopathies. Clinical data, genetic findings, and survival were analysed using Kaplan–Meier curves.

A total of 45 cases, male predominance (55.6%), and mean age at diagnosis of 6.5 years. Dilated and hypertrophic cardiomyopathy were the most common (33.3%). The main reason for diagnosis was the investigation of cardiovascular symptoms (60.9%). Genetic investigation occurred in 66.6%, a positivity rate of 60%. Multi-organ/system involvement was significantly associated with a positive genetic result (77.7%, p = 0.017). Mortality was 11.1%; survival was significantly lower in the following conditions: ejection fraction < 30% (p < 0.0001), functional class III/IV (p < 0.0001), heart failure (p = 0.0091), use of three or more cardiovascular medications (p < 0.001), N-Terminal Pro-B-Type natriuretic peptide >1000pg/mL (p = 0.004), and heart transplant indication (p < 0.001).

These findings provide novel data in Brazil, highlight a high rate of positive genetic test, particularly among patients with systemic involvement and identify key clinical predictors of mortality to guide risk stratification and care.