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
{"title":"Meta-analysis of genome-wide associations and polygenic risk prediction for atrial fibrillation in more than 180,000 cases","authors":"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","doi":"10.1038/s41588-024-02072-3","DOIUrl":null,"url":null,"abstract":"<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>","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"67 1","pages":""},"PeriodicalIF":31.7000,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Nature genetics","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1038/s41588-024-02072-3","RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"GENETICS & HEREDITY","Score":null,"Total":0}
引用次数: 0
Abstract
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.
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Nature Genetics publishes the very highest quality research in genetics. It encompasses genetic and functional genomic studies on human and plant traits and on other model organisms. Current emphasis is on the genetic basis for common and complex diseases and on the functional mechanism, architecture and evolution of gene networks, studied by experimental perturbation.
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