Polygenic Mediation Analysis of Psychological Resilience and Outcomes in Taiwanese Young Adults

Polygenic risk scores (PRSs) for psychiatric phenotypes correlate with state psychological outcomes, with resilience mediating this relationship, suggesting that genetic predisposition may increase mental health risk via lower resilience. Using national genome-wide data from Taiwan Biobank (TWB), we built PRS for psychiatric diagnosis (PD), major depressive disorder (MDD), bipolar disorder (BD), obsessive-compulsive disorder (OCD), and schizophrenia (SCZ) based on single-nucleotide polymorphisms (SNPs) associated with psychiatric phenotypes. To test our hypothesis, we conducted polygenic mediation models in a locally recruited cohort of young adults (N = 159, mean age = 23.0), applying False Discovery Rate (FDR) correction. Resilience (mediator) measures included the Connor-Davidson Resilience Scale (CD-RISC) and the Resilience Scale for Adults (RSA). Psychological outcomes were assessed with the Beck Depression Inventory (BDI) and Beck Anxiety Inventory (BAI). Mediation analysis showed that resilience significantly mediated the relationship between PRS-PD and BAI, where the indirect effects via CD-RISC was 0.47 (95% CI [confidence interval]: 0.04-0.97; p = 0.036) and via RSA was 0.51 (95% CI: 0.09-1.09; p = 0.020). PRS-MDD and BAI, with indirect effects via CD-RISC (1.96 [95% CI: 0.47-4.22]; p = 0.033) and RSA (0.33 [95% CI: 0.03-2.93]; p = 0.048). PRS-OCD and BAI were mediated via RSA (0.09 [95% CI: 0.02-0.18]; p = 0.009). We also found significant mediation effects via RSA for PRS-SCZ and BAI (0.69 [95% CI: 0.10-1.44]; p = 0.024) and PRS-SCZ and BDI (1.16 [95% CI: 0.01-0.33]; p = 0.042), but not after FDR correction. These findings highlight that resilience mitigates the genetic predisposition to depression and anxiety, emphasizing the importance of interventions to enhance resilience in individuals predisposed to psychiatric phenotypes.