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 Müller-Nurasyid, J Gustav Smith, Jennifer A Brody, Maartje N Niemeijer, Marcus Dörr, Stella Trompet, Jennifer Huffman, Stefan Gustafsson, Claudia Schurmann, Marcus E Kleber, Leo-Pekka Lyytikäinen, Ilkka Seppälä, Rainer Malik, Andrea R V R Horimoto, Marco Perez, 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 Sun, Jemma C Hopewell, Stephanie Debette, Ganesh Chauhan, Qiong Yang, Bradford B Worrall, Guillaume Paré, 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 Kähönen, 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 Magnusson, David 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 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 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 Pereira, J Wouter Jukema, Caroline Hayward, Jerome I Rotter, Winfried März, Terho Lehtimäki, Bruno H Stricker, Mina K Chung, Stephan B Felix, Vilmundur Gudnason, Alvaro 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

Atrial fibrillation affects more than 33 million people worldwide and increases the risk of stroke, heart failure, and death. Fourteen genetic loci have been associated with atrial fibrillation in European and Asian ancestry groups. 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 discovery.