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

Poeya Haydarlou; Daria R. Kramarenko; Nobuyuki Enzan; Marie Klevjer; Oliver B. Vad; Marre E. Corver; Dominic S. Zimmerman; Takayuki Morisaki; Yukinori Okada; Yoichiro Kamatani; Kaori Muto; Akiko Nagai; Yoji Sagiya; Natsuhiko Kumasaka; Yoichi Furukawa; Yuji Yamanashi; Yoshinori Murakami; Yusuke Nakamura; Wataru Obara; Ken Yamaji; Kazuhisa Takahashi; Satoshi Asai; Yasuo Takahashi; Shinichi Higashiue; Shuzo Kobayashi; Hiroki Yamaguchi; Yasunobu Nagata; Satoshi Wakita; Chikako Nito; Yu-ki Iwasaki; Shigeo Murayama; Kozo Yoshimori; Yoshio Miki; Daisuke Obata; Masahiko Higashiyama; Akihide Masumoto; Yoshinobu Koga; Yukihiro Koretsune; Koichi Matsuda; Søren Z. Diederichsen; Anja Bye; Jesper H. Svendsen; Kaoru Ito; Patrick T. Ellinor; Connie R. Bezzina; Sean J. Jurgens

doi:10.1038/s41467-026-72708-x

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

P Poeya Haydarlou D Daria R. Kramarenko N Nobuyuki Enzan M Marie Klevjer O Oliver B. Vad M Marre E. Corver D Dominic S. Zimmerman T Takayuki Morisaki Y Yukinori Okada Y Yoichiro Kamatani K Kaori Muto A Akiko Nagai Y Yoji Sagiya N Natsuhiko Kumasaka Y Yoichi Furukawa (Division of Clinical Genome Research, Center for Experimental Medicine and Systems Biology, The Institute of Medical Science, The University of Tokyo) Y Yuji Yamanashi Y Yoshinori Murakami Y Yusuke Nakamura (Division of Life Science, Graduate School of Science and Engineering, Saitama University) W Wataru Obara K Ken Yamaji K Kazuhisa Takahashi S Satoshi Asai Y Yasuo Takahashi S Shinichi Higashiue S Shuzo Kobayashi H Hiroki Yamaguchi Y Yasunobu Nagata S Satoshi Wakita C Chikako Nito Y Yu-ki Iwasaki S Shigeo Murayama K Kozo Yoshimori Y Yoshio Miki D Daisuke Obata M Masahiko Higashiyama A Akihide Masumoto Y Yoshinobu Koga Y Yukihiro Koretsune K Koichi Matsuda S Søren Z. Diederichsen A Anja Bye J Jesper H. Svendsen K Kaoru Ito P Patrick T. Ellinor C Connie R. Bezzina S Sean J. Jurgens

Abstract

Abstract 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.

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Article Details

Journal Nature Communications

Volume / Issue Vol. 17, Issue 1

Published May 05, 2026

DOI 10.1038/s41467-026-72708-x

ISSN 2041-1723

Publisher Nature Portfolio

Journal Info

Nature Communications

Nature Portfolio

ISSN: 2041-1723 Open Access Life Sciences

Authors (46)

P

Poeya Haydarlou

D

Daria R. Kramarenko

N

Nobuyuki Enzan

M

Marie Klevjer

O

Oliver B. Vad

M

Marre E. Corver

D

Dominic S. Zimmerman

T

Takayuki Morisaki

Y

Yukinori Okada

Y

Yoichiro Kamatani

K

Kaori Muto

A

Akiko Nagai

Y

Yoji Sagiya

N

Natsuhiko Kumasaka

Y

Yoichi Furukawa

Division of Clinical Genome Research, Center for Experimental Medicine and Systems Biology, The Institute of Medical Science, The University of Tokyo

Y

Yuji Yamanashi

Y

Yoshinori Murakami

Y

Yusuke Nakamura

Division of Life Science, Graduate School of Science and Engineering, Saitama University

W

Wataru Obara

K

Ken Yamaji

K

Kazuhisa Takahashi

S

Satoshi Asai

Y

Yasuo Takahashi

S

Shinichi Higashiue

S

Shuzo Kobayashi

H

Hiroki Yamaguchi

Y

Yasunobu Nagata

S

Satoshi Wakita

C

Chikako Nito

Y

Yu-ki Iwasaki

S

Shigeo Murayama

K

Kozo Yoshimori

Y

Yoshio Miki

D

Daisuke Obata

M

Masahiko Higashiyama

A

Akihide Masumoto

Y

Yoshinobu Koga

Y

Yukihiro Koretsune

K

Koichi Matsuda

S

Søren Z. Diederichsen

A

Anja Bye

J

Jesper H. Svendsen

K

Kaoru Ito

P

Patrick T. Ellinor

C

Connie R. Bezzina

S

Sean J. Jurgens

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

Abstract

Article Details

Journal Info

Authors (46)

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