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Multi-phenotype analyses of hemostatic traits with cardiovascular events reveal novel genetic associations

Gerard Temprano Sagrera, Collen M. Sitlani, William P. Bone, Miguel Martín Bórnez, Benjamin Voight, Alanna Morrison, Scott M. Damrauer, Paul S. de Vries, Nicholas L. Smith, Maria Sabater-Lleal, Abbas Dehghan, Adam S. Heath, Alex P. Reiner, Andrew Johnson, Anne Richmond, Annette Peters, Astrid van Hylckama Vlieg, Barbara McKnight, Bruce M. Psaty, Caroline HaywardCavin Ward-Caviness, Cristopher O'Donnell, Daniel Chasman, David P. Strachan, David A. Tregouet, Dennis Mook-Kanamori, Dipender Gill, Florian Thibord, Folkert W. Asselbergs, Frank W. G. Leebeek, Frits Rosendaal, Gail Davies, Georg Homuth, Gerard Temprano Sagrera, Harry Campbell, Herman A. Taylor, Jan Bressler, Jennifer E. Huffman, Jerome I. Rotter, Jie Yao, James F. Wilson, Joshua C. Bis, Julie M. Hahn, Karl C. Desch, Kerri L. Wiggins, Laura M. Raffield, Lawrence F. Bielak, Lisa R. Yanek, Marcus E. Kleber, Martina Mueller, Maryam Kavousi, Massimo Mangino, Melissa Liu, Michael R. Brown, Matthew P. Conomos, Min-A. Jhun, Ming-Huei Chen, Moniek P. M. de Maat, Nathan Pankratz, Patricia A. Peyser, Paul Elliot, Peng Wei, Philipp S. Wild, Pierre E. Morange, Pim van der Harst, Qiong Yang, Ngoc-Quynh Le, Riccardo Marioni, Ruifang Li, Scott M. Damrauer, Simon R. Cox, Stella Trompet, Stephan B. Felix, Uwe Völker, Weihong Tang, Wolfgang Koenig, J. Wouter Jukema, Xiuqing Guo, Sara Lindstrom, Lu Wang, Erin N. Smith, William Gordon, Mariza de Andrade, Jennifer A. Brody, Jack W. Pattee, Jeffrey Haessler, Ben M. Brumpton, Pierre Suchon, Constance Turman, Marine Germain, James MacDonald, Sigrid K. Braekkan, Sebastian M. Armasu, Rebecca D. Jackson, Jonas B. Nielsen, Franco Giulianini, Marja K. Puurunen, Manal Ibrahim, Susan R. Heckbert, Theo K. Bammler, Kelly A. Frazer, Bryan M. McCauley, Kent Taylor, James S. Pankow, Alexander P. Reiner, Maiken E. Gabrielsen, Jean-François Deleuze, Chris J. O'Donnell, Jihye Kim, Peter Kraft, John-Bjarne Hansen, John A. Heit, Charles Kooperberg, Kristian Hveem, Paul M. Ridker, Pierre-Emmanuel Morange, Andrew D. Johnson, Christopher Kabrhel, David-Alexandre Trégouët, Rainer Malik, Ganesh Chauhan, Matthew Traylor, Muralidharan Sargurupremraj, Yukinori Okada, Aniket Mishra, Loes Rutten-Jacobs, Anne-Katrin Giese, Sander W. van der Laan, Solveig Gretarsdottir, Christopher D. Anderson, Michael Chong, Hieab H. H. Adams, Tetsuro Ago, Peter Almgren, Philippe Amouyel, Hakan Ay, Traci M. Bartz, Oscar R. Benavente, Steve Bevan, Giorgio B. Boncoraglio, Robert D. Brown, Aadam S. Butterworth, Caty Carrera, Cara L. Carty, Wei-Min Chen, John W. Cole, Adolfo Correa, Ioanna Cotlarciuc, Carlos Cruchaga, John Danesh, Paul I. W. de Bakker, Anita L. DeStefano, Marcel den Hoed, Qing Duan, Stefan T. Engelter, Guido J. Falcone, Rebecca F. Gottesman, Raji P. Grewal, Vilmundur Gudnason, S. Gustafsson, Tamara B. Harris, Ahamad Hassan, Aki S. Havulinna, Elizabeth G. Holliday, George Howard, Fang-Chi Hsu, Hyacinth I. Hyacinth, M. Arfan Ikram, Erik Ingelsson, Marguerite R. Irvin, Xueqiu Jian, Jordi Jimenez-Conde, Julie A. Johnson, Masahiro Kanai, Keith L. Keene, Brett M. Kissela, Dawn O. Kleindorfer, Michiaki Kubo, Leslie A. Lange, Carl D. Langefeld, Claudia Langenberg, Lenore J. Launer, Jin-Moo Lee, Robin Lemmens, Didier Leys, Cathryn M. Lewis, Wei-Yu Lin, Arne G. Lindgren, Erik Lorentzen, Patrik K. Magnusson, Jane Maguire, Ani Manichaikul, Patrick F. McArdle, James F. Meschia, Braxton Mitchell, Thomas H. Mosley, Michael A. Nalls, Toshiharu Ninomiya, Martin J. O'Donnell, Sara L. Pulit, Kristiina Rannikmäe, Kathryn M. Rexrode, Kenneth Rice, Stephen S. Rich, Natalia S. Rost, Peter M. Rothwell, Tatjana Rundek, Ralph L. Sacco, Saori Sakaue, Michele M. Sale, Veikko Salomaa, Bishwa R. Sapkota, Reinhold Schmidt, Carsten O. Schmidt, Ulf Schminke, Pankaj Sharma, Agnieszka Slowik, Cathie L. M. Sudlow, Christian Tanislav, Turgut Tatlisumak, Vincent N. S. Thijs, Gudmar Thorleifsson, Unnur Thorsteinsdottir, Steffen Tiedt, Christophe Tzourio, Cornelia M. van Duijn, Matthew Walters, Nicholas J. Wareham, Sylvia Wassertheil-Smoller, James G. Wilson, Salim Yusuf, Najaf Amin, Hugo S. Aparicio, Donna Arnett, John Attia, Alexa S. Beiser, Claudine Berr, Julie E. Buring, Mariana Bustamante, Valeria Caso, Yu-Ching Cheng, Seung Hoan Choi, Ayesha Chowhan, Natalia Cullell, Jean-François Dartigues, Hossein Delavaran, Pilar Delgado, Marcus Dörr, Gunnar Engström, Ian Ford, Wander S. Gurpreet, Anders Hamsten, Laura Heitsch, Aatsushi Hozawa, Laura Ibanez, Andrea Ilinca, Martin Ingelsson, Motoki Iwasaki, Katarina Jood, Pekka Jousilahti, Sara Kaffashian, Lalit Kalra, Masahiro Kamouchi, Takanari Kitazono, Olafur Kjartansson, Manja Kloss, Peter J. Koudstaal, Jerzy Krupinski, Daniel L. Labovitz, Cathy C. Laurie, Christhoper R. Levi, Linxin Li, Lars Lind, Cecilia M. Lindgren, Vasileios Lioutas, Yong Mei Liu, Oscar L. Lopez, Hirata Makoto, Nicolas Martinez-Majander, Koichi Matsuda, Naoko Minegishi, Joan Montaner, Andrew P. Morris, Elena Muiño, Martina Müller-Nurasyid, Bo Norrving, Soichi Ogishima, Eugenio A. Parati, Leema Reddy Peddareddygari, Nancy L. Pedersen, Joanna Pera, Markus Perola, Alessandro Pezzini, Silvana Pileggi, Raquel Rabionet, Iolanda Riba Llena, Marta Ribasés Haro, Jose R. Romero, Anthony G. Rudd, Antti-Pekka Sarin, Ralhan Sarju, Chloe Sarnowski, Makoto Sasaki, Claudia L. Satizabal, Mamoru Satoh, Naveed Sattar, Norie Sawada, Gerli Sibolt, Ásgeir Sigurdsson, Albert Smith, Kenji Sobue, Carolina Soriano Tárraga, Tara Stanne, O. Colin Stine, David J. Stott, Konstantin Strauch, Takako Takai, Hideo Tanaka, Kozo Tanno, Alexander Teumer, Liisa Tomppo, Nuria P. Torres-Aguila, Emmanuel Touze, Shoichiro Tsugane, Aandre G. Uitterlinden, Einar M. Valdimarsson, Sven J. van der Lee, Henry Völzke, Kenji Wakai, David Weir, Stephen R. Williams, Charles D.A. Wolfe, Quenna Wong, Huichun Xu, Taiki Yamaji, Dharambir K. Sanghera, Olle Melander, Christina Jern, Daniel Strbian, Israel Fernandez-Cadenas, W.T. Longstreth, Arndt Rolfs, Jun Hata, Daniel Woo, Jonathan Rosand, Guillaume Paré, Jemma C. Hopewell, Danish Saleheen, Kári Stefánsson, BradfordB. Worrall, Steven J. Kittner, Sudha Seshadri, Myriam Fornage, Hugh S. Markus, Joana M. M. Howson, Yoichiro Kamatani, Stéphanie Debette, Martin Dichgans

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Resum

Multi-phenotype analysis of genetically correlated phenotypes can increase the statistical power to detect loci associated with multiple traits, leading to the discovery of novel loci. This is the first study to date to comprehensively analyze the shared genetic effects within different hemostatic traits, and between these and their associated disease outcomes. To discover novel genetic associations by combining summary data of correlated hemostatic traits and disease events. Methods: Summary statistics from genome wide-association studies (GWAS) from seven hemostatic traits (factor VII [FVII], factor VIII [FVIII], von Willebrand factor [VWF] factor XI [FXI], fibrinogen, tissue plasminogen activator [tPA], plasminogen activator inhibitor 1 [PAI-1]) and three major cardiovascular (CV) events (venous thromboembolism [VTE], coronary artery disease [CAD], ischemic stroke [IS]), were combined in 27 multi-trait combinations using metaUSAT. Genetic correlations between phenotypes were calculated using Linkage Disequilibrium Score Regression (LDSC). Newly associated loci were investigated for colocalization. We considered a significance threshold of 1.85 × 10 obtained after applying Bonferroni correction for the number of multi-trait combinations performed (n = 27). Across the 27 multi-trait analyses, we found 4 novel pleiotropic loci (XXYLT1, KNG1, SUGP1/MAU2, TBL2/MLXIPL) that were not significant in the original individual datasets, were not described in previous GWAS for the individual traits, and that presented a common associated variant between the studied phenotypes. The discovery of four novel loci contributes to the understanding of the relationship between hemostasis and CV events and elucidate common genetic factors between these traits.
Idioma originalAnglès
Pàgines (de-a)1331-1349
Nombre de pàgines19
RevistaJournal of Thrombosis and Haemostasis
Volum20
Número6
DOIs
Estat de la publicacióPublicada - 2022

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