Multi-trait polygenic risk scores improve genomic prediction of atrial fibrillation across diverse ancestries.

Polygenic scores can improve atrial fibrillation risk prediction. However, limited accuracy and cross-ancestry transferability hinder clinical translation. Here, we explore several ensemble approaches to generate ancestry-optimized polygenic scores, with development in diverse participants from the All of Us Research Program, BioBank Japan, and three additional cohorts. Our ancestry-specific multi-trait approach particularly improves prediction in South-Asian (odds-ratio/standard deviation 1.5-1.8; area under curve 0.60-0.64; relative R² +71%), Admixed-American (1.5; 0.60; +34%) and African ancestry groups (1.4; 0.57; +56%). Nevertheless, performance remains highest in European and East-Asian ancestries (1.8-2.2; 0.65-0.68), where >50% of SNP-heritability is explained. Improved risk stratification is also observed at the extremes, identifying European and East-Asian ancestry individuals with risk comparable to rare TTN variants (e.g., 6-11% with >4-fold odds). Finally, our scores improve incident risk prediction alongside clinical models. Together, we show that our ancestry-tailored multi-trait polygenic scores advance atrial fibrillation risk prediction and stratification, providing an equitable foundation for implementation.
Cardiovascular diseases
Care/Management

Authors

Haydarlou Haydarlou, Kramarenko Kramarenko, Enzan Enzan, Klevjer Klevjer, Vad Vad, Corver Corver, Zimmerman Zimmerman, , Matsuda Matsuda, Diederichsen Diederichsen, Bye Bye, Svendsen Svendsen, Ito Ito, Ellinor Ellinor, Bezzina Bezzina, Jurgens Jurgens
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