Investigating Pathway-Partitioned Polygenic Risk Scores for Schizophrenia: Insights into Clinical Variability in Two Patient Cohorts

Background: Differences in age of psychosis onset (AOO) in schizophrenia (SCZ) are associated with different illness trajectories. Determining whether AOO differences can be explained by genome-wide or pathway-partitioned polygenic risk for SCZ (SCZ-PRS) may elucidate mechanisms underlying clinical variability. This study examined relationships between AOO, genome-wide SCZ-PRS, and pathway-partitioned SCZ-PRS in a harmonized, multi-ancestry North American dataset (SCZ-NA) and in UK Biobank (SCZ-UKBB). Methods: For each cohort, we computed one genome-wide SCZ-PRS and 18 mutually-exclusive pathway-based PRS derived from previous published and validated neurodevelopmental gene-sets. We evaluated 13 SNP-to-gene mapping strategies, including comparing non-coding SNP-to-gene mappings informed by functional annotations versus distance-based windows. SCZ case-control prediction and AOO associations were tested using logistic and linear mixed models, respectively, controlling for sex, ancestry principal components, and genetic relatedness. Results: Genome-wide SCZ-PRS robustly predicted SCZ case-control status in both cohorts but not AOO. In contrast, pathway-based analyses identified AOO associations for a fetal angiogenesis and a postnatal synaptic signaling and plasticity gene-set across both cohorts (p < .05), alongside nominal cohort-specific associations in other gene-sets. Associations depended on SNP-to-gene mapping definitions; experimentally informed strategies, particularly those incorporating brain expression Quantitative Trait Locus (eQTL) annotations performed best. Conclusion: Findings suggest that neurovascular and postnatal synaptic signaling and refinement mechanisms contribute to AOO variation in SCZ, and that pathway-informed PRS, especially with brain-specific non-coding SNP-to-gene mappings, can help identify mechanisms contributing to variability in AOO. Replication in larger, prospectively phenotyped cohorts with harmonized AOO definitions will further clarify genetic mechanisms underlying clinical variability in SCZ.