interaction

Novel Method: The paper introduces Pathway Polygenic Risk Scores (pPRS), a targeted method for GxE analysis that restricts genetic variants to specific, biologically informed genomic pathways.
Increased Power: Simulations and empirical analysis demonstrated that pPRS yields substantially greater statistical power to detect true GxE interactions compared to using a standard, overall PRS.
Empirical Example: The method identified a significant interaction between pPRS based on the TGF-\(\beta\)/GRHR pathway and NSAID use for colorectal cancer (CRC) risk, suggesting the strongest protective effect of NSAIDs in those with high pathway-specific genetic risk.

PIGEON Framework: The paper introduces PIGEON, a unified statistical framework that uses a variance component analytical approach to quantify polygenic Gene-Environment Interaction (GxE).
Input and Scalability: PIGEON is highly scalable as its estimation procedure requires only GWAS and GWIS summary statistics (not individual-level data).
Key Objectives: The framework provides rigorous methods for both detecting the presence of GxE (by estimating GxE variance) and interpreting its mechanism (by estimating Oracle PGSxE), demonstrating its utility across multiple empirical settings including gene-by-sex and gene-by-education studies.