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

2017; Nature Portfolio; Volume: 49; Issue: 6 Linguagem: Inglês

10.1038/ng.3843

1546-1718

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 Weeke, Martina Müller‐Nurasyid, J. G. Smith, Jennifer A. Brody, Maartje N. Niemeijer, Marcus Dörr, Stella Trompet, Jennifer E. Huffman, Stefan Gustafsson, Claudia Schurmann, Marcus E. Kleber, Leo‐Pekka Lyytikäinen, Ilkka Seppälä, Rainer Malik, Andréa R. V. R. Horimoto, Marco Pérez, Juha Sinisalo, Stefanie Aeschbacher, Sébastien Thériault, 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 Y. Sun, Jemma C. Hopewell, Stéphanie Debette, Ganesh Chauhan, Qiong Yang, Bradford B. Worrall, Guillaume Paré, Yoichiro Kamatani, Yanick 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, Mélanie Waldenberger, Peter Lichtner, Marina Arendt, José Eduardo Krieger, Mika Kähönen, Lorenz Risch, Alfredo José Mansur, Annette Peters, Blair H. Smith, Lars Lind, Stuart A. Scott, Yingchang Lu, Erwin B. Bottinger, Jussi Hernesniemi, Cecilia M. Lindgren, Jorge 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 S. 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, André G. Uitterlinden, Albert Hofman, Oscar H. Franco, Uwe Völker, Karl‐Heinz Jöckel, 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 C. Pereira, J. Wouter Jukema, Caroline Hayward, Jerome I. Rotter, Winfried März, Terho Lehtimäki, Bruno H. Stricker, Mina K. Chung, Stephan B. Felix, Vilmundur Guðnason, Álvaro Alonso, Dan M. Roden, Stefan Kääb, Daniel I. Chasman, Susan R. Heckbert, Emelia J. Benjamin, Toshihiro Tanaka, Kathryn L. Lunetta, Steven A. Lubitz, Patrick T. Ellinor,

Genetic Associations and Epidemiology

Patrick Ellinor and colleagues report meta-analyses of common and rare variant association studies for atrial fibrillation across multiple populations. They identify 12 new loci, some of which implicate genes in atrial electrical and mechanical function. Atrial fibrillation affects more than 33 million people worldwide and increases the risk of stroke, heart failure, and death1,2. Fourteen genetic loci have been associated with atrial fibrillation in European and Asian ancestry groups3,4,5,6,7. To further define the genetic basis of atrial fibrillation, we performed large-scale, trans-ancestry meta-analyses of common and rare variant association studies. The genome-wide association studies (GWAS) included 17,931 individuals with atrial fibrillation and 115,142 referents; the exome-wide association studies (ExWAS) and rare variant association studies (RVAS) involved 22,346 cases and 132,086 referents. We identified 12 new 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 atrial fibrillation, provide insights into the molecular basis of atrial fibrillation, and may facilitate the identification of new potential targets for drug discovery8.