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 (PRSEA), cognitive reserve (CR), and clinical symptoms are associated with psychosocial functioning in first-episode psychosis (FEP). Nevertheless, the mechanisms underlying their complex interaction is yet to be explored. This study aimed to assess the mediating role of CR and clinical symptoms, both negative (NS) and positive (PS), on the interrelationship between PRSEA 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 (GWAS) summary results, PRSEA were constructed for each individual. Two mediation models were explored. The parallel mediation model explored the relationship of PRSEA with functionality through CR and clinical symptoms, NS, and PS. 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 PRSEA > CR > NS > Functionality (β=-0.35, 95%CI [-0.85, -0.04], p<0.05). The model fit the data satisfactorily (CFI=1.00; RMSEA=0.00; SRMR=7.2x10-7). Conversely, in a parallel mediation, none of the three mediators significantly mediated the relationship between PRSEA 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 PRSEA 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.