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

Area of Science:

• Psychiatric Genetics
• Neuroscience
• Bioinformatics

Background:

• Age of psychosis onset (AOO) in schizophrenia (SCZ) is linked to distinct illness trajectories.
• Understanding the genetic underpinnings of AOO variation is crucial for elucidating SCZ mechanisms.
• This study investigates the role of genome-wide and pathway-partitioned polygenic risk scores (PRS) in AOO.

Purpose of the Study:

• To determine if genome-wide and pathway-partitioned SCZ-PRS explain differences in AOO.
• To identify specific biological pathways associated with AOO variation in SCZ.
• To evaluate the impact of different SNP-to-gene mapping strategies on PRS associations with AOO.

Main Methods:

• Calculated genome-wide SCZ-PRS and 18 pathway-based PRS from neurodevelopmental gene sets.
• Employed 13 SNP-to-gene mapping strategies, including functional annotations and distance-based windows.
• Utilized logistic and linear mixed models to test SCZ prediction and AOO associations, controlling for covariates.

Main Results:

• Genome-wide SCZ-PRS predicted SCZ status but not AOO.
• Pathway-based analyses identified significant AOO associations for fetal angiogenesis and postnatal synaptic signaling gene sets.
• The best performance for SNP-to-gene mapping involved experimentally informed strategies, particularly those using brain eQTL data.

Conclusions:

• Neurovascular and postnatal synaptic signaling mechanisms contribute to AOO variation in SCZ.
• Pathway-informed PRS, especially with brain-specific mappings, can uncover genetic mechanisms underlying SCZ clinical variability.
• Replication in larger cohorts with harmonized AOO definitions is needed to confirm findings.