Michael O’Donovan

The association of schizophrenia polygenic scores with continuously-hospitalized, treatment-resistant schizophrenia.

More than 20% of individuals with schizophrenia show minimal or no response to antipsychotic medications and little is known about genetic contributions to more severe forms of illness. This study sought to explore if cases with continuously-hospitalized, treatment-resistant schizophrenia (CH-TRS) carry a higher burden of common genetic variants compared to less severe forms. CH-TRS cases were recruited from Pennsylvania state psychiatric hospitals in the USA, with ≥ 5 years of continuous hospitalization, active treatment, and non-response to ≥ 3 antipsychotic medications. Three comparator groups were obtained from cohorts in the USA, Sweden, and the UK including TRS, general schizophrenia and non-psychiatric controls. Polygenic scores (PGS) of schizophrenia and cognitive ability were generated in individuals of European and African ancestry. Logistic regression assessed the association of PGS and CH-TRS cases (vs. comparators), with sex differences and sensitivity analyses excluding individuals with other diagnoses conducted to assess robustness. We included 18,571 individuals of European ancestry (346 CH-TRS, 10,757 TRS, 1148 general schizophrenia, 6320 non-psychiatric controls) and exploratory analyses of 476 individuals of African ancestry (78 CH-TRS, 398 non-psychiatric controls). For each standard deviation increase in the schizophrenia PGS, the odds of CH-TRS among individuals of European ancestry increased by 40-80% compared to general schizophrenia and TRS. Results in African ancestry participants mirrored those of European ancestry albeit with reduced levels of significance. Sex interactions and sensitivity analyses did not materially alter the estimates. This study demonstrates a greater burden of common genetic variants is associated with more severe forms of illness in schizophrenia.

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.

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