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

Polygenic risk meets early trauma: toward a neuropsychodevelopmental model of schizophrenia.

Advances in psychiatric genetics have substantially reshaped current models of schizophrenia-spectrum disorders, shifting the focus from single risk factors to polygenic liability and its interaction with environmental adversity. Polygenic risk scores (PRS) provide a quantitative index of genetic vulnerability; however, how this liability interfaces with early-life stress-particularly childhood trauma-across neurodevelopment remains insufficiently conceptualized. Accumulating evidence indicates that the interplay between polygenic risk and childhood trauma influences not only the likelihood of psychosis onset but also the emergence of specific symptom dimensions during clinical high-risk states and early stages of illness. Yet, existing theoretical frameworks tend to consider genetic predisposition and environmental exposure as parallel or additive processes, offering limited insight into their developmental convergence. In this Perspective, we examine current neurodevelopmental models of schizophrenia and integrate them within a unified framework, proposing that polygenic liability, environmental exposures (including early trauma), and psychological processes interact dynamically and bidirectionally across sensitive developmental windows, shaping distinct neuropsychodevelopmental trajectories. Integrating polygenic, environmental, and developmental domains within a unified neuropsychodevelopmental framework may help explain clinical heterogeneity, with important implications for early identification, risk stratification, and personalized preventive strategies.

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

Prolonged CAL is linked to higher risk of FEP, preferentially affective psychosis in females, poorer functioning, and developmental potentiation of polygenic liability.

Evaluating the performance of polygenic indices of neuropsychiatric conditions and brain endophenotypes in four UK population samples

Genetic architecture of externalizing and internalizing traits in the general population and its link to psychiatric conditions and well-being: a multivariate approach.

Externalizing and internalizing behaviours capture heritable, transdiagnostic dimensions of psychopathology, but their genetic architecture and links to societal outcomes remain incompletely understood. This study applied a multivariate framework to population-based, non-clinical traits to explore simultaneous genetic associations across externalizing and internalizing behaviours to elucidate their biological underpinnings and genetic relation to clinical diagnoses. Using genomic structural equation modelling, we built a two-factor model for externalizing (EXT) and internalizing (INT) behaviour utilizing 13 genome-wide association study (GWAS) summary statistics from population-based cohorts (n=64,000-1,200,000). We tested genetic correlations of EXT and INT with 12 psychiatric diagnoses (n=14,000-2,000,000) using linkage-disequilibrium score regression, and we studied genetic relation to emotional well-being with polygenic score analyses (PRS-CS) in an independent cohort (n= 4,565). Multivariate GWAS revealed 184 genome-wide significant loci for EXT and 31 for INT. Gene-level analyses identified 52 novel genes for EXT and 18 for INT. Enrichment analyses using single-cell-RNA-sequencing data showed significant enrichment in neuronal and non-neuronal populations, with strongest signals in hippocampal CA4 for EXT and amygdalar excitatory neurons for INT. EXT correlated with attention-deficit/hyperactivity disorder and substance-use disorders, INT showed significant genetic correlations with obsessive-compulsive disorder and anorexia nervosa. EXT and INT also exhibited overlap in genetic correlations with posttraumatic stress disorder, major depressive disorder, schizophrenia, and anxiety disorder. PRS-CS demonstrated association of INT liability with emotional well-being. Overall, these findings advance our understanding of the genetic architecture underlying transdiagnostic externalizing and internalizing behaviours and underscore their relevance for both psychiatric risk and emotional well-being.

Genome-wide association analyses of borderline personality disorder identify 11 loci and highlight shared risk with mental and somatic disorders

BPD showed the strongest positive genetic correlations with GWAS of post-traumatic stress disorder, depression, attention deficit hyperactivity disorder, antisocial behavior, antisocial behavior, and measures of suicide and self-harm.

Disorder-specific and shared genetic architecture underlying schizophrenia and bipolar disorder

Schizophrenia (SCZ) and bipolar disorder (BIP) share substantial common-variant liability but differ in cognition, medical comorbidity, and treatment response. Here we decomposed this overlap into schizophrenia-predominant, bipolar-predominant, and shared psychosis dimensions to test whether these components show distinct pleiotropic and biological profiles. Using the largest available SCZ and BIP GWAS, we applied bidirectional mtCOJO and Genomic SEM to derive SCZcondBIP, BIPcondSCZ, and PSY-shared and validated them using inter-component genetic correlations, FinnGen psychiatric endpoints, and Genomic SEM latent factors. We then characterized each component across cognitive, cardiometabolic, and immune traits, followed by genomic risk-locus discovery, pathway analysis, developmental expression profiling, and drug-target enrichment. The three components showed marked divergence. SCZcondBIP was negatively genetically correlated with cognition, education, metabolic syndrome, C-reactive protein, and neutrophil percentage, whereas BIPcondSCZ showed the opposite cognitive profile and shifted toward positive cardiometabolic and immune correlations. PSY-shared retained the mixed cognitive pattern seen at the disorder level and intermediate peripheral correlations, indicating that shared psychosis liability masks stronger disorder-specific differences. Between-component contrasts were approximately twice the magnitude of the corresponding SCZ-versus-BIP contrasts. We identified 248 consensus genomic risk loci, including 81 not detected in the input disorder GWAS. Biologically, PSY-shared was enriched for synaptic signalling, ion-channel, and neurodevelopmental pathways; SCZcondBIP primarily implicated synaptic-signalling and cellular-homeostasis pathways; and BIPcondSCZ showed weaker but distinct enrichment for synaptic-vesicular biology. Drug-target enrichment further separated the components, with strong antipsychotic enrichment for PSY-shared and distinct non-antipsychotic signals for the conditional factors. These findings show that SCZ and BIP genetic risk is best understood as biologically distinguishable shared and disorder-predominant dimensions that differentially map onto cognitive, cardiometabolic, immune, and molecular architecture. These findings provide a framework for evaluating whether component-specific polygenic scores improve stratification of cognitive, cardiometabolic, and inflammatory heterogeneity across severe psychiatric illness.