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.