Instability of high polygenic risk classification and mitigation by integrative scoring

Anika Misra, Buu Truong, Sarah M. Urbut, Yang Sui, Akl C. Fahed, Jordan W. Smoller, Aniruddh P. Patel () and Pradeep Natarajan ()
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Anika Misra: Broad Institute of MIT and Harvard
Buu Truong: Broad Institute of MIT and Harvard
Sarah M. Urbut: Broad Institute of MIT and Harvard
Yang Sui: Broad Institute of MIT and Harvard
Akl C. Fahed: Broad Institute of MIT and Harvard
Jordan W. Smoller: Massachusetts General Hospital
Aniruddh P. Patel: Broad Institute of MIT and Harvard
Pradeep Natarajan: Broad Institute of MIT and Harvard

Nature Communications, 2025, vol. 16, issue 1, 1-12

Abstract: Abstract Polygenic risk scores (PRS) continue to improve with novel methods and expanding genome-wide association studies. Healthcare and commercial laboratories are increasingly deploying PRS reports to patients, but it is unknown how the classification of high polygenic risk changes across individual PRS. Here, we assess the association and classification performance of cataloged PRS for three complex traits. We chronologically order all trait-related publications (Pubn) and identify the single PRS Best(Pubn) for each Pubn that has the strongest association with the target outcome. While each Best(Pubn) demonstrates generally consistent population-level strengths of associations, the classification of individuals in the top 10% of each Best(Pubn) distribution varies widely. Using the PRSmix framework, which integrates information across several PRS to improve prediction, we generate corresponding ChronoAdd(Pubn) scores for each Pubn that combine all polygenic scores from all publications up to and including Pubn. When compared with Best(Pubn), ChronoAdd(Pubn) scores demonstrate more consistent high-risk classification amongst themselves. This integrative scoring approach provides stable and reliable classification of high-risk individuals and is an adaptable framework into which new scores can be incorporated as they are introduced, integrating easily with current PRS implementation strategies.

Date: 2025
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DOI: 10.1038/s41467-025-56945-0

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