PRANA: A Deep Learning Method for Adapting Polygenic Risk Scores to Diverse Ethnic Groups

Area of Science:

• Genomics
• Computational Biology
• Precision Medicine

Background:

• Polygenic risk scores (PRSs) assess inherited disease susceptibility but show reduced accuracy in non-European populations due to genetic architecture differences.
• Genome-wide association studies (GWAS) predominantly feature European cohorts, leading to inequities in PRS deployment.
• Existing cross-ancestry PRS methods often require large target population datasets or perform suboptimally.

Purpose of the Study:

• To introduce PRANA (Polygenic Risk Adaptation via Neural-network Architecture), a deep learning framework designed to adapt existing PRS models to new ancestries.
• To address the challenge of reduced PRS predictive accuracy in underrepresented populations.
• To provide a scalable and practical solution for equitable genomic risk prediction.

Main Methods:

• PRANA utilizes a deep learning framework to adapt pre-trained PRS models (derived from European cohorts) to other ancestries.
• The adaptation process leverages modestly sized cohorts from the target population, avoiding the need for large-scale GWAS in those groups.
• The framework was evaluated on seven complex traits across South Asian, East Asian, and Ashkenazi Jewish populations, including small East Asian subpopulations.

Main Results:

• PRANA demonstrated improvements in predictive performance, typically enhancing effect size (β) and Nagelkerke's R² by 5%-20% compared to baseline PRS models.
• In most evaluations, PRANA outperformed existing cross-ancestry multi-PRS approaches.
• The framework proved effective even in challenging scenarios with scarce training data within specific East Asian subpopulations.

Conclusions:

• PRANA offers a scalable and practical strategy to enhance the predictive accuracy of PRS across diverse ancestries.
• The framework effectively reduces disparities in genomic risk prediction, promoting more equitable applications of PRS.
• PRANA represents a significant step towards advancing precision medicine in underrepresented global populations.