Multiancestry transferability of a polygenic risk score for diverticulitis

Area of Science:

• Genetics and Genomics
• Gastroenterology
• Population Health

Background:

• Polygenic risk scores (PRS) require validation in diverse populations to ensure equitable clinical application.
• Diverticular disease (DD) exhibits a complex etiology influenced by genetic and environmental factors.

Purpose of the Study:

• To evaluate a 44-variant PRS for diverticular disease in the diverse "All of Us" Research Program cohort.
• To explore phenome-wide associations with DD genetic susceptibility.
• To assess the PRS's ability to stratify risk for symptomatic and severe diverticulitis across different ancestral groups.

Main Methods:

• A 44-variant PRS was applied to 181,719 individuals for phenome-wide association studies (PheWAS) and 50,037 for risk modeling.
• PheWAS identified conditions genetically linked to DD, including connective tissue diseases and hernias.
• Logistic regression models incorporating PRS were compared to baseline models using AUROC and Nagelkerke's R² for performance assessment.

Main Results:

• The PRS demonstrated consistent associations with increased odds of symptomatic and severe diverticulitis across European, African, and Admixed-American ancestries.
• Phenome-wide analysis revealed genetic links between DD, connective tissue disorders, and hernias.
• European ancestry models yielded the highest performance metrics (AUROC: 0.78, R²: 0.25), with PRS contributing a modest R² increase of 0.034.

Conclusions:

• A diverticular disease PRS effectively identifies individuals at higher genetic risk for severe disease presentations, even after accounting for traditional risk factors.
• The PRS offers relative improvements in risk stratification models across diverse populations.
• Absolute performance enhancements from the PRS were modest, indicating potential for future refinement and integration with other risk predictors.