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bioRxiv · 10.1101/2025.10.15.682516

MAP-PRS: Multi-Ancestry Portfolio-Based Polygenic Risk Scores

Thakur, L. S.·Singh, N.·Bharj, G.
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Abstract

Polygenic Risk Scores (PRS) are emerging tools for predicting an individuals genetic risk for complex diseases. However, their usefulness in clinical practice remains limited because most existing models are based on data from people of European ancestry, leading to reduced accuracy and stability in other populations. This imbalance restricts the equitable use of PRS in precision medicine. To overcome these limitations, we introduce Multi-Ancestry Portfolio-Based Polygenic Risk Scores (MAP-PRS)--a new framework that combines mathematical modeling and data science principles to improve both fairness and reliability in genetic risk prediction across populations. MAP-PRS treats each ancestry-specific PRS as part of a "portfolio," similar to how investments are managed in finance, balancing two key aspects: predictive return (how well the score predicts disease) and risk complexity (how uncertain or ancestry-specific the prediction is). By jointly optimizing these factors, MAP-PRS identifies the best combination of ancestry-informed PRS models that maximize predictive accuracy while minimizing bias and instability. This approach also uses advanced computational tools--such as Bayesian modeling, machine learning, and generative neural networks--to refine risk estimates, incorporate environmental and lifestyle factors, and increase representation from under-studied populations. In doing so, MAP-PRS supports more inclusive, equitable, and interpretable precision medicine. As an initial demonstration, MAP-PRS has been applied to predict Type 2 Diabetes (T2D) risk in European ancestry populations, establishing a foundation for broader, multi-ancestry implementation. Future extensions will include additional diseases, such as cervical cancer and HPV susceptibility, endometrioid ovarian cancer, and Alzheimers disease--bringing us closer to clinically actionable and globally equitable genetic risk prediction.

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Thakur, L. S., Singh, N., Bharj, G.. 2025-10-15. MAP-PRS: Multi-Ancestry Portfolio-Based Polygenic Risk Scores. https://doi.org/10.1101/2025.10.15.682516

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