Introduction Limitations of current classifications of schizophrenia, schizoaffective disorder, and bipolar disorder are evident from their overlapping symptoms, aetiologies, treatments, and outcomes, and present a barrier to novel treatment discovery. Alternative conceptualisations are needed to address nosological validity, align diagnosis to aetiology, and improve prognostication and treatment choice. We aimed to identify latent classes across the psychosis spectrum based on premorbid functioning and outcomes, and assess these in relation to genetic liability and symptom dimensions. Method Participants with a diagnosis of schizophrenia, schizoaffective disorder, or bipolar disorder type 1, were ascertained from four UK clinical cohorts (total n=5,043). Latent class analysis was conducted using phenotypes not included within the diagnostic criteria, including premorbid functioning, age at illness onset, and measures of severity and course. Polygenic scores (PGS) for psychiatric disorders and behavioural traits were tested for associations with latent classes. We tested if diagnosis explained associations between PGS and classes. Results A three-class model provided the best fit. Class one had poorer premorbid functioning, lower rates of recovery, and higher PGS for schizophrenia and ADHD. Class three had the highest functioning, higher rates of psychosocial stressors before onset, higher intelligence PGS and lower PGS for psychiatric disorders. Class two was intermediate between classes one and three on measures of functioning, but was characterised by high levels of involuntary hospital admissions and high bipolar disorder PGS. Diagnosis only partially explained associations between PGS and class membership. Conclusions We identified classes across the psychosis spectrum characterised by different premorbid functioning and outcomes, that cut across diagnostic categories and captured genetic liability not explained by diagnosis. Our findings suggest alternative conceptualisations of psychotic disorders may complement diagnoses in mapping to the aetiology of these conditions, and could be useful to advance precision psychiatry.
Charlotte A. Dennison, S. Legge, A. Cardno et al.· medRxiv· 0 citations
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.
G. Trotta, I. Austin-Zimmerman, E. Spinazzola et al.· Translational Psychiatry· 0 citations
Prolonged CAL is linked to higher risk of FEP, preferentially affective psychosis in females, poorer functioning, and developmental potentiation of polygenic liability.
Á. Andreu-Bernabeu, J. González-Peñas, M. Bernardo et al.· Schizophrenia bulletin· 0 citations