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Atrial Fibrillation Genetic Risk Differentiates Cardioembolic Stroke from other Stroke Subtypes

By Sara L Pulit, Lu-Chen Weng, Patrick F McArdle, Ludovic Trinquart, Seung Hoan Choi, Braxton D Mitchell, Jonathan Rosand, Paul I. W. de Bakker, Emelia J. Benjamin, Patrick T Ellinor, Steven J Kittner, Steven A. Lubitz, Christopher D. Anderson, on behalf of the Atrial Fibrillation Genetics Consortium and the International Stroke Genetics Consortium, 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, Sebastian Clauss, Rajat Deo, Daniel J Rader, Svati Shah, 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, arju Orho-Melander, Anders Hamsten, Jan Heeringa, Joshua C. Denny, Jennifer Kriebel, Dawood Darbar, Christopher Newton-Cheh, Christian Shaffer, Peter W. Macfarlane, Stefanie Heilmann, 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, 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, Albert Sun, Stefan Kääb, Jemma C. Hopewell, Stephanie Debette, Ganesh Chauhan, Qiong Yang, Bradford B. Worrall, Guillaume Paré, Yoichiro Kamatani, Yanick P. Hagemeijer, Niek Verweij, Kent D Taylor, Archie Campbell, Patrik K Magnusson, David Porteous, Lynne J. Hocking, Efthymia Vlachopoulou, Nancy L. Pedersen, Kjell Nikus, Daniel I Chasman, Susan R Heckbert, Toshihiro Tanaka, Kathryn L. Lunetta, Sylvia Smoller, John Sorkin, Xingwu Wang, Magdy Selim, Aleksandra Pikula, Philip Wolf, Sudha Seshadri, Paul de Bakker, Sara L Pulit, Daniel Chasman, Kathryn Rexrode, Ida Chen, Jerome Rotter, May Luke, Michelle Sale, Tsong-Hai Lee, Ku-Chou Chang, Mitchell Elkind, Larry Goldstein, Michael Luke James, Monique Breteler, Chris O’Donnell, Didier Leys, Cara Carty, Chelsea Kidwell, Jes Olesen, Pankaj Sharma, Stephen Rich, Turgot Tatlisumak, Olli Happola, Philippe Bijlenga, Carolina Soriano, Eva Giralt, Jaume Roquer, Jordi Jimenez-Conde, Ioana Cotlarcius, John Hardy, Michal Korostynski, Giorgio Boncoraglio, Elena Ballabio, Eugenio Parati, Adamski Mateusz, Andrzej Urbanik, Tomasz Dziedzic, Jeremiasz Jagiella, Jerzy Gasowski, Marcin Wnuk, Rafael Olszanecki, Joanna Pera, Agnieszka Slowik, Karol Jozef Juchniewicz, Christopher Levi, Paul Nyquist, Iscia Cendes, Norberto Cabral, Paulo Franca, Anderson Goncalves, Lina Keller, Milita Crisby, Konstantinos Kostulas, Robin Lemmens, Kourosh Ahmadi, Christian Opherk, Marco Duering, Mariya Gonik, Julie Staals, Philippe Burri, Ariane Sadr-Nabavi, Javier Romero, Alessandro Biffi, Chris Anderson, Guido Falcone, Bart Brouwers, Rose Du, Christina Kourkoulis, Thomas Battey, Steven Lubitz, Bertram Mueller-Myhsok, James Meschia, Thomas Brott, Guillaume Pare, Alexander Pichler, Christian Enzinger, Helena Schmidt, Reinhold Schmidt, Stephan Seiler, Susan Blanton, Yoshiji Yamada, Anna Bersano, Tatjana Rundek, Ralph Sacco, Yu-Feng Yvonne Chan, Andreas Gschwendtner, Zhen Deng, Taura Barr, Katrina Gwinn, Roderick Corriveau, Andrew Singleton, Salina Waddy, Lenore Launer, Christopher Chen, Kim En Le, Wei Ling Lee, Eng King Tan, Akintomi Olugbodi, Peter Rothwell, Sabrina Schilling, Vincent Mok, Elena Lebedeva, Christina Jern, Katarina Jood, Sandra Olsson, Helen Kim, Chaeyoung Lee, Laura Kilarski, Hugh Markus, Jennifer Peycke, Steve Bevan, Wayne Sheu, Hung Yi Chiou, Joseph Chern, Elias Giraldo, Muhammad Taqi, Vivek Jain, Olivia Lam, George Howard, Daniel Woo, Steven Kittner, Braxton Mitchell, John Cole, Jeff O’Connell, Dianna Milewicz, Kachikwu Illoh, Bradford Worrall, Colin Stine, Bartosz Karaszewski, David Werring, Reecha Sofat, June Smalley, Arne Lindgren, Bjorn Hansen, Bo Norrving, Gustav Smith, Juan Jose Martin, Vincent Thijs, Karin Klijn, Femke van’t Hof, Ale Algra, Mary Macleod, Rodney Perry, Donna Arnett, Alessandro Pezzini, Alessandro Padovani, Steve Cramer, Mark Fisher, Danish Saleheen, Joseph Broderick, Brett Kissela, Alex Doney, Sudlow Cathie, Kristiina Rannikmae, Scott Silliman, Caitrin McDonough, Matthew Walters, Annie Pedersen, Kazuma Nakagawa, Christy Chang, Mark Dobbins, Patrick McArdle, Yu-Ching Chang, Robert Brown, Devin Brown, Elizabeth Holliday, Raj Kalaria, Jane Maguire, Attia John, Martin Farrall, Anne-Katrin Giese, Myriam Fornage, Jennifer Majersik, Mary Cushman, Keith Keene, Siiri Bennett, David Tirschwell, Bruce Psaty, Alex Reiner, Will Longstreth, David Spence, Joan Montaner, Israel Fernandez-Cadenas, Carl Langefeld, Cheryl Bushnell, Laura Heitsch, Jin-Moo Lee, Kevin Sheth

Posted 24 Dec 2017
bioRxiv DOI: 10.1101/239269 (published DOI: 10.1212/nxg.0000000000000293)

Atrial fibrillation is a prevalent arrhythmia associated with a five-fold increased risk of ischemic stroke, and specifically the cardioembolic stroke subtype. Genome-wide association studies of these traits have yielded overlapping risk loci, but genome-wide investigation of genetic susceptibility shared between stroke and atrial fibrillation is lacking. Comparing the genetic architectures of the two diseases could inform whether cardioembolic strokes are driven by inherited atrial fibrillation susceptibility, and may help elucidate ischemic stroke mechanisms. Here, we analyze genome-wide genotyping data and estimate SNP-based heritability in atrial fibrillation and cardioembolic stroke to be nearly identical (20.0% and 19.5%, respectively). Further, we find that the traits are genetically correlated (r=0.77 for SNPs with p < 4.4 x 10-4 in a previous atrial fibrillation meta-analysis). Clinical studies are warranted to assess whether genetic susceptibility to atrial fibrillation can be leveraged to improve the diagnosis and care of ischemic stroke patients.

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