The Role of Cognitive Reserve and Clinical Symptoms in the Association Between Genetic Liability for Educational Attainment and Functioning in First-episode Psychosis: A Mediation Analysis

Background: Polygenic risk scores for educational attainment (PRS), cognitive reserve (CR), and clinical symptoms are associated with functioning in first-episode psychosis (FEP). Nevertheless, the mechanisms underlying their complex interaction are yet to be explored. This study assessed the mediating role of CR and clinical symptoms, both negative (NS) and positive (PS), on the interrelationship between PRS and functionality, one year after a FEP.

Methods: A total of 162 FEP patients underwent clinical, functional, and genetic assessments. Using genome-wide association study summary results, PRS were constructed for each individual. Two mediation models were performed. The parallel mediation model explored the relationship of PRS with functionality through CR and clinical symptoms. The serial mediation model tested a causal chain of the three mediators: CR, NS, and PS. Mediation analysis was performed using the PROCESS function V.4.1 in SPSS V.22.

Results: A serial mediation model revealed a causal chain for PRS > CR > NS > Functionality ( = -0.35, 95%CI [-0.85, -0.04],  < 0.05). The model fit the data satisfactorily (CFI = 1.00; RMSEA = 0.00; SRMR = 7.2 × 10). Conversely, no parallel mediation was found between the three mediators, PRS and functionality and the model poorly fit the data (CFI = 0.30; RMSEA = 0.25; SRMR = 0.11).

Conclusions: Both CR and NS mediate the relationship between PRS and functionality at one-year follow-up, using serial mediation analysis. This may be relevant for prevention and personalized early intervention to reduce illness impact and improve functional outcomes in FEP patients.