Genetic Signatures Predict Social-Cognitive Trajectories in Ultra-High-Risk Psychosis: A 24-month Longitudinal Study

Abstract

Background Identifying biomarkers that predict social and cognitive outcomes in individuals at ultra-high risk (UHR) for psychosis remains a key challenge in preventive psychiatry. While genetic factors contribute to psychosis vulnerability, specific markers that predict individual trajectories of functional decline or resilience are still unclear. Methods In a 24-month longitudinal study involving UHR (n=45) and healthy control participants (n=54), we investigated for the first time the predictive causal relationship between key immunological genes (FABP5 family and immunoglobulins) and social-cognitive outcomes. Participants completed comprehensive assessments at baseline and four 6-month intervals. We used regression modelling and dynamic Bayesian network analysis to identify predictive relationships between gene expression and behavioral outcomes over time. Results FABP5 family genes (FABP5P1, FABP5P11, FABP5P9) significantly predicted verbal memory (β=0.233, p=0.002); working memory (β=0.225, p=0.004), and social skills (β =-0·190, p<0.029), respectively, at 24 months in the UHR group. Immunoglobulin-related genes showed distinct effects: FCGR2B predicted object recognition ability (β=0.233, p=0.014), while GOT2 inversely predicted planning ability (β=-0.147, p=0.067). Network analysis revealed UHR-specific temporal dependencies absent in controls, with FCGRT emerging as a central node linking genetic markers to changes in processing speed and perceptual closure. Conclusions This study provides the first evidence that FABP5 and immunoglobulin-related genetic markers can predict social-cognitive trajectories in individuals at risk for psychosis. These findings support the use of genetic profiling for early identification and highlight new opportunities for personalized preventive strategies in psychiatry.