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

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.

Childhood maltreatment and joint trajectories of social isolation and depression as predictors of cognitive impairment in late midlife: a prospective cohort study

Abstract Aims Childhood maltreatment has been associated with increased risk of cognitive impairment in later life, but little is known about whether distinct joint trajectories of social isolation and depression across midlife predict this risk. Methods Using a prospective cohort design with documented childhood maltreatment and matched controls (N = 1196) followed from ages 0 to 11 into late midlife, we modelled joint trajectories of social isolation and depression (ages 29–47) using group-based trajectory modelling (GBTM) and examined their associations with cognitive impairment with no dementia (CIND) at age 59 through modified Poisson regression, controlling for risk factors related to neurodegenerative outcomes (i.e., hypertension, diabetes, obesity, limited physical activity, hearing impairment, smoking, excessive alcohol consumption and traumatic brain injury). Results GBTM identified four groups: ‘Not isolated or depressed’ (67.7%), ‘Moderately isolated’ (11.7%), ‘Moderately depressed’ (16.5%) and ‘Chronically isolated and depressed’ (4.1%). Using the ‘Not isolated or depressed’ group as the reference category, membership in the highest-risk trajectory (‘Chronically isolated and depressed’) was associated with a 41.5% higher risk of CIND, whereas the ‘Moderately isolated’ and ‘Moderately depressed’ groups did not differ significantly from the reference group. Black non-Hispanic participants and those with documented childhood maltreatment histories had 32.8% and 21.2% higher risk of CIND, respectively, and each additional year of education was associated with a 4.9% reduction in CIND risk. Conclusions Sustained co-occurring social isolation and depression from early to mid-adulthood predicted increased risk of CIND independent of established risk factors, highlighting prolonged social and emotional difficulties as modifiable targets for late midlife cognitive health.

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.

Adolescents at the crossroads: genetic associations between psychotic symptoms and antisocial traits.

Antisocial behaviour in youth has serious consequences at individual and societal level. Adolescence is also a critical period for the emergence of prodromal psychosis symptoms. Their co-occurrence may aggravate aggression and lead to severe adverse outcomes. Common genetic risk for psychosis, antisocial behaviour, and substance use has been suggested, but the putatively shared genetic architecture is unknown, and evidence in youth is limited. Here we examined whether common genetic liability indexed by polygenic risk scores (PRSs) relates to these complex traits in the Norwegian Mother, Father and Child Cohort Study (MoBa; n = 18960). Antisocial psychopathology was operationalised as three complementary dimensions: conduct-disorder (CD) traits, oppositional-defiant disorder (ODD) traits, and psychopathy traits. We first quantified phenotypic correlations between psychotic-like experiences (PLEs) and the antisocial dimensions. We then evaluated PRS-phenotype associations (single-PRS and joint multivariable models) using PRSs for antisocial behaviour (PRSASB) and schizophrenia (PRSSCZ), in addition to PRS for alcohol use disorder (PRSAUD). We found phenotypic correlations between antisocial traits and PLEs (rs=0.13-0.34, p < 0.0001). This overlap was reflected at the genetic level, as we found associations between PRSASB and PLEs (p = 0.0004). The associations between PRSSCZ and antisocial traits were present for CD (p = 0.005) and ODD (p = 0.003) traits. Both PLEs and antisocial traits were associated with PRSAUD. Patterns persisted in mutually adjusted models. These findings indicate cross-trait associations between polygenic liability for SCZ, ASB, AUD and adolescent PLEs and antisocial dimensions in the general youth population, consistent with partially shared common genetic influences. Future studies should further delineate underlying biological mechanisms.

Persistence of psychotic experiences and clinical outcomes in adolescents at familial high risk of schizophrenia or bipolar disorder: The Danish High Risk and Resilience Study

Alcohol use disorder and childhood adversity in the association between polygenic risk and suicidality.

OBJECTIVE Suicidal ideation (SI) and suicide attempt (SA) are both influenced by genetic, behavioral, and environmental factors. Alcohol use disorder (AUD) and adverse childhood experiences (ACEs) may mediate or moderate the effects of genetic liability for suicidality. METHODS Using data from 10,275 participants (43.8% female; 47.2% African-like genetic ancestry [AFR], 52.8% European-like genetic ancestry [EUR]), we tested whether polygenic scores (PGS) for SI and SA predicted lifetime suicidality outcomes. We evaluated whether AUD partially accounted for these associations and ACEs moderated the direct and indirect associations. RESULTS The SA PGS was significantly associated with SA (AFR: b = 0.36, SE = 0.01; EUR: b = 0.17, SE = 0.01; both ps < 2e-16), but the SI PGS was not associated with SI (p > 0.55). AUD statistically mediated the association between the SA PGS and SA, accounting for approximately 2% of the total association in AFR individuals and 10% in EUR individuals (both ps < 2e-16). Notably, the proportion of the association that was accounted for by AUD decreased as ACEs exposure increased, from 4.30% to 0.54% in AFR individuals and from 13.31% to 3.44% in EUR individuals. In contrast, there was only very modest mediation and no moderated mediation for SI. CONCLUSIONS Particularly among individuals with lower ACEs exposure, AUD accounted for a meaningful proportion of the association between genetic liability to SA and lifetime SA. These findings highlight different correlates across suicidality phenotypes and suggest potential clinical relevance for AUD in the association between genetic liability and SA.