T77. POLYGENIC AND ENVIRONMENTAL PREDICTORS OF CLINICAL AND FUNCTIONAL OUTCOMES FOLLOWING FIRST-EPISODE PSYCHOSIS

While most research has focused on identifying risk factors for the onset of psychosis, there remains a significant gap in understanding predictors of long-term outcomes following FEP. The heterogeneity of outcomes poses a challenge, due to the lack of consensus on which outcome domains are most clinically meaningful or prognostically relevant. Furthermore, genetic and environmental factors influencing these varied long-term outcomes remain largely unexplored in an integrated manner. To address this gap, we aim to develop aggregate scores that capture clinical and functional outcomes five years after FEP. We analysed data from the Genetics and Psychosis (GAP) study, comprising 353 first episodes of psychosis that were followed up for 5 years. A confirmatory factor analysis (CFA) was performed to examine the loadings on two pre-defined latent factors representing clinical and functional outcomes. Polygenic risk scores (PGS) were calculated using PRScs methods via the GenoPred pipeline for 174 participants of African and European ancestry. PGS were constructed using summary statistics from the largest available genome-wide association studies for schizophrenia, bipolar disorder (BD), major depressive disorder (by the Psychiatric Genomics Consortium), and IQ. Maudsley Environmental Risk Score was used as an aggregate score of pre-onset environmental stressors that have been most robustly associated with psychosis. Medication adherence was used as a post-onset environmental predictor. We conducted univariate and multivariate linear regression analyses for both factors. All analyses were adjusted for sex, age, ethnicity and the first 10 principal components. CFA confirmed that six outcome measures reliably loaded onto the two factors. The clinical outcomes factor was defined by the number of episodes per year, antipsychotic switching frequency, and days admitted to hospital per year. The functioning factor was characterized by independent living status, global assessment of functioning (GAF) scores, and whether psychosis had affected participants’ relationships with family or friends. Linear regression analyses demonstrated that higher polygenic scores for BD predicted a decrease in clinical outcome severity (ß=0.09, p=0.046. This association was further strengthened after adjusting for other PGS and environmental predictors (ß=0.13, p=0.010). No other genetic or environmental predictors reached statistical significance for the clinical outcome factor. Female sex (ß=0.31, p=0.004) and medication compliance (ß=0.21, p=0.04) emerged as significant predictors of better functional outcomes. Our findings suggest that females and individuals that adhere to medication experience significantly better functional outcomes following FEP. Higher genetic risk for BD appeared protective for worse clinical outcomes. Ongoing work aims to isolate the genetic liability for BD from the substantial shared genetic risk with schizophrenia using genomic structural equation modeling. This approach aims to improve predictions of clinical outcomes in psychosis.