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.
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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