Large-scale analyses of common and rare variants identify 12 new loci associated with atrial fibrillation

Ingrid E. Christophersen, Michiel Rienstra, Carolina Roselli, Xiaoyan Yin, Bastiaan Geelhoed, John Barnard, Honghuang Lin, Dan E. Arking, Albert V. Smith, Christine M. Albert, Mark Chaffin, Nathan R. Tucker, Molong Li, Derek Klarin, Nathan A. Bihlmeyer, Siew-Kee Low, Peter E. Weeke, Martina Mueller-Nurasyid, J. Gustav Smith, Jennifer A. BrodyMaartje N. Niemeijer, Marcus Doerr, Stella Trompet, Jennifer E. Huffman, Stefan Gustafsson, Claudia Schurmann, Marcus E. Kleber, Leo-Pekka Lyytikainen, Ilkka Seppala, Rainer Malik, Andrea R. V. R. Horimoto, Marco Perez, Juha Sinisalo, Stefanie Aeschbacher, Sebastien Theriault, Jie Yao, Farid Radmanesh, Stefan Weiss, Alexander Teumer, Seung Hoan Choi, Lu-Chen Weng, Sebastian Clauss, Rajat Deo, Daniel J. Rader, Svati H. Shah, Albert Sun, Jemma C. Hopewell, Stephanie Debette, Ganesh Chauhan, Qiong Yang, Bradford B. Worrall, Guillaume Pare, Yoichiro Kamatani, Yanick P. Hagemeijer, Niek Verweij, Joylene E. Siland, Michiaki Kubo, Jonathan D. Smith, David R. Van Wagoner, Joshua C. Bis, Siegfried Perz, Bruce M. Psaty, Paul M. Ridker, Jared W. Magnani, Tamara B. Harris, Lenore J. Launer, M. Benjamin Shoemaker, Sandosh Padmanabhan, Jeffrey Haessler, Traci M. Bartz, Melanie Waldenberger, Peter Lichtner, Marina Arendt, Jose E. Krieger, Mika Kahonen, Lorenz Risch, Alfredo J. Mansur, Annette Peters, Blair H. Smith, Lars Lind, Stuart A. Scott, Yingchang Lu, Erwin B. Bottinger, Jussi Hernesniemi, Cecilia M. Lindgren, Jorge A. Wong, Jie Huang, Markku Eskola, Andrew P. Morris, Ian Ford, Alex P. Reiner, Graciela Delgado, Lin Y. Chen, Yii-Der Ida Chen, Roopinder K. Sandhu, Man Li, Eric Boerwinkle, Lewin Eisele, Lars Lannfelt, Natalia Rost, Christopher D. Anderson, Kent D. Taylor, Archie Campbell, Patrik K. E. Magnusson, David J. Porteous, Lynne J. Hocking, Efthymia Vlachopoulou, Nancy L. Pedersen, Kjell Nikus, Marju Orho-Melander, Anders Hamsten, Jan Heeringa, Joshua C. Denny, Jennifer Kriebel, Dawood Darbar, Christopher Newton-Cheh, Christian M. Shaffer, Peter W Macfarlane, Stefanie Heilmann-Heimbach, Peter Almgren, Paul L. Huang, Nona Sotoodehnia, Elsayed Z. Soliman, Andre G. Uitterlinden, Albert Hofman, Oscar H. Franco, Uwe Voelker, Karl-Heinz Joeckel, Moritz F. Sinner, Henry J Lin, Xiuqing Guo, Martin Dichgans, Erik Ingelsson, Charles Kooperberg, Olle Melander, Ruth J. F. Loos, Jari Laurikka, David Conen, Jonathan Rosand, Pim van der Harst, Marja-Liisa Lokki, Sekar Kathiresan, Alexandre Pereira, J. Wouter Jukema, Caroline Hayward, Jerome I. Rotter, Winfried Maerz, Terho Lehtimaki, Bruno H. C. Stricker, Mina K. Chung, Stephan B. Felix, Vilmundur Gudnason, Alvaro Alonso, Dan M. Roden, Stefan Kaeaeb, Daniel I. Chasman, Susan R. Heckbert, Emelia J. Benjamin, Toshihiro Tanaka, Kathryn L. Lunetta, Steven A. Lubitz, Patrick T. Ellinor

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    Abstract

    Atrial fibrillation (AF) affects more than 33 million people worldwide and increases the risk of stroke, heart failure, and death.1,2 Fourteen genetic loci have been associated with AF in European and Asian ancestry groups.3–7 To further define the genetic basis of AF, we performed large-scale, multi-racial meta-analyses of common and rare variant association studies. The genome-wide association studies (GWAS) included 18,398 individuals with AF and 91,536 referents; the exome-wide association studies (ExWAS) and rare variant association studies (RVAS) involved 22,806 cases and 132,612 referents. We identified 12 novel genetic loci that exceeded genome-wide significance, implicating genes involved in cardiac electrical and structural remodeling. Our results nearly double the number of known genetic loci for AF, provide insights into the molecular basis of AF, and may facilitate new potential targets for drug discovery.
    Original languageEnglish
    Pages (from-to)946-952
    Number of pages7
    JournalNature Genetics
    Volume49
    Issue number6
    Early online date17 Apr 2017
    DOIs
    Publication statusPublished - Jun 2017

    Keywords

    • Atrial fibrillation
    • population genetics
    • genome-wide association studies
    • gene expression

    Cite this

    Christophersen, I. E., Rienstra, M., Roselli, C., Yin, X., Geelhoed, B., Barnard, J., Lin, H., Arking, D. E., Smith, A. V., Albert, C. M., Chaffin, M., Tucker, N. R., Li, M., Klarin, D., Bihlmeyer, N. A., Low, S-K., Weeke, P. E., Mueller-Nurasyid, M., Smith, J. G., ... Ellinor, P. T. (2017). Large-scale analyses of common and rare variants identify 12 new loci associated with atrial fibrillation. Nature Genetics, 49(6), 946-952. https://doi.org/10.1038/ng.3843