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<p>Atrial fibrillation (AF) is the most common heart rhythm abnormality and is a leading cause of heart failure and stroke. This large-scale meta-analysis of genome-wide association studies increased the power to detect single-nucleotide variant associations and found more than 350 AF-associated genetic loci. We identified candidate genes related to muscle contractility, cardiac muscle development and cell–cell communication at 139 loci. Furthermore, we assayed chromatin accessibility using assay for transposase-accessible chromatin with sequencing and histone H3 lysine 4 trimethylation in stem cell-derived atrial cardiomyocytes. We observed a marked increase in chromatin accessibility for our sentinel variants and prioritized genes in atrial cardiomyocytes. Finally, a polygenic risk score (PRS) based on our updated effect estimates improved AF risk prediction compared to the CHARGE-AF clinical risk score and a previously reported PRS for AF. The doubling of known risk loci will facilitate a greater understanding of the pathways underlying AF.</p>

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Meta-analysis of genome-wide associations and polygenic risk prediction for atrial fibrillation in more than 180,000 cases

  • 期刊论文

  • 发表日期：

    2025年3月6日

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  • Carolina Roselli,
  • Ida Surakka,
  • Morten S. Olesen,
  • Gardar Sveinbjornsson,
  • Nicholas A. Marston,
  • Seung Hoan Choi,
  • Hilma Holm,
  • Mark Chaffin,
  • Daniel Gudbjartsson,
  • Matthew C. Hill,
  • Hildur Aegisdottir,
  • Christine M. Albert,
  • Alvaro Alonso,
  • Christopher D. Anderson,
  • Dan E. Arking,
  • David O. Arnar,
  • John Barnard,
  • Emelia J. Benjamin,
  • Eugene Braunwald,
  • Ben Brumpton,
  • Archie Campbell,
  • Nathalie Chami,
  • Daniel I. Chasman,
  • Kelly Cho,
  • Eue-Keun Choi,
  • Ingrid E. Christophersen,
  • Mina K. Chung,
  • David Conen,
  • Harry J. Crijns,
  • Michael J. Cutler,
  • Tomasz Czuba,
  • Scott M. Damrauer,
  • Martin Dichgans,
  • Marcus Dörr,
  • Elton Dudink,
  • ThuyVy Duong,
  • Christian Erikstrup,
  • Tõnu Esko,
  • Diane Fatkin,
  • Jessica D. Faul,
  • Manuel Ferreira,
  • Daniel F. Freitag,
  • Santhi K. Ganesh,
  • J. Michael Gaziano,
  • Bastiaan Geelhoed,
  • Jonas Ghouse,
  • Christian Gieger,
  • Franco Giulianini,
  • Sarah E. Graham,
  • Vilmundur Gudnason,
  • Xiuqing Guo,
  • Christopher Haggerty,
  • Caroline Hayward,
  • Susan R. Heckbert,
  • Kristian Hveem,
  • Kaoru Ito,
  • Renee Johnson,
  • J. Wouter Jukema,
  • Sean J. Jurgens,
  • Stefan Kääb,
  • John P. Kane,
  • Shinwan Kany,
  • Sharon L. R. Kardia,
  • Maryam Kavousi,
  • Shaan Khurshid,
  • Frederick K. Kamanu,
  • Paulus Kirchhof,
  • Marcus E. Kleber,
  • Stacey Knight,
  • Issei Komuro,
  • Jose E. Krieger,
  • Lenore J. Launer,
  • Dadong Li,
  • Honghuang Lin,
  • Henry J. Lin,
  • Ruth J. F. Loos,
  • Luca Lotta,
  • Steven A. Lubitz,
  • Kathryn L. Lunetta,
  • Peter W. Macfarlane,
  • Patrik K. E. Magnusson,
  • Rainer Malik,
  • Helene Mantineo,
  • Gregory M. Marcus,
  • Winfried März,
  • David D. McManus,
  • Olle Melander,
  • Giorgio E. M. Melloni,
  • Pascal B. Meyre,
  • Kazuo Miyazawa,
  • Sanghamitra Mohanty,
  • Laia M. Monfort,
  • Martina Müller-Nurasyid,
  • Navid A. Nafissi,
  • Andrea Natale,
  • Saman Nazarian,
  • Sisse R. Ostrowski,
  • Hui-Nam Pak,
  • Shichao Pang,
  • Ole B. Pedersen,
  • Nancy L. Pedersen,
  • Alexandre C. Pereira,
  • James P. Pirruccello,
  • Michael Preuss,
  • Bruce M. Psaty,
  • Clive R. Pullinger,
  • Daniel J. Rader,
  • Joel T. Rämö,
  • Paul M. Ridker,
  • Michiel Rienstra,
  • Lorenz Risch,
  • Dan M. Roden,
  • Jerome I. Rotter,
  • Marc S. Sabatine,
  • Heribert Schunkert,
  • Svati H. Shah,
  • Jaemin Shim,
  • M. Benjamin Shoemaker,
  • Bridget Simonson,
  • Moritz F. Sinner,
  • Roelof A. J. Smit,
  • Jennifer A. Smith,
  • Nicholas L. Smith,
  • J. Gustav Smith,
  • Elsayed Z. Soliman,
  • Erik Sørensen,
  • Nona Sotoodehnia,
  • Daniel Strbian,
  • Bruno H. Stricker,
  • Maris Teder-Laving,
  • Yan V. Sun,
  • Sébastien Thériault,
  • Rosa B. Thorolfsdottir,
  • Unnur Thorsteinsdottir,
  • Arnljot Tveit,
  • Pim van der Harst,
  • Joyce van Meurs,
  • Biqi Wang,
  • Stefan Weiss,
  • Quinn S. Wells,
  • Lu-Chen Weng,
  • Peter W. Wilson,
  • Ling Xiao,
  • Pil-Sung Yang,
  • Jie Yao,
  • Zachary T. Yoneda,
  • Tanja Zeller,
  • Lingyao Zeng,
  • Wei Zhao,
  • Xiang Zhou,
  • Sebastian Zöllner,
  • Christian T. Ruff,
  • Henning Bundgaard,
  • Cristen Willer,
  • Kari Stefansson,
  • Patrick T. Ellinor

摘要

Atrial fibrillation (AF) is the most common heart rhythm abnormality and is a leading cause of heart failure and stroke. This large-scale meta-analysis of genome-wide association studies increased the power to detect single-nucleotide variant associations and found more than 350 AF-associated genetic loci. We identified candidate genes related to muscle contractility, cardiac muscle development and cell–cell communication at 139 loci. Furthermore, we assayed chromatin accessibility using assay for transposase-accessible chromatin with sequencing and histone H3 lysine 4 trimethylation in stem cell-derived atrial cardiomyocytes. We observed a marked increase in chromatin accessibility for our sentinel variants and prioritized genes in atrial cardiomyocytes. Finally, a polygenic risk score (PRS) based on our updated effect estimates improved AF risk prediction compared to the CHARGE-AF clinical risk score and a previously reported PRS for AF. The doubling of known risk loci will facilitate a greater understanding of the pathways underlying AF.