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

Gerard Temprano-Sagrera, Colleen M. Sitlani, William P. Bone, Miguel Martin-Bornez, Benjamin F. Voight, Alanna C. Morrison, Scott M. Damrauer, Paul S. de Vries, Nicholas L. Smith, Maria Sabater-Lleal, Abbas Dehghan, Adam S. Heath, Alanna C. Morrison, Alex P. Reiner, Andrew Johnson, Anne Richmond, Annette Peters, Astrid van Hylckama Vlieg, Barbara McKnight, Bruce M. PsatyCaroline Hayward, Cavin Ward-Caviness, Christopher 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 R. Rosendaal, Gail Davies, Georg Homuth, Gerard Temprano, 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, Maria Sabater-Lleal, 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, Nicholas L. Smith, Patricia A. Peyser, Paul Elliot, Paul S. de Vries, 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, Astrid van Hylckama Vlieg, Mariza de Andrade, Jennifer A. Brody, Jack W. Pattee, Jeffrey Haessler, Ben M. Brumpton, Daniel I. Chasman, Pierre Suchon, Ming Huei Chen, Constance Turman, Marine Germain, Kerri L. Wiggins, James MacDonald, Sigrid K. Braekkan, Sebastian M. Armasu, Nathan Pankratz, Rabecca 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, Barbara McKnight, Peter Kraft, John Bjarne Hansen, Frits R. Rosendaal, John A. Heit, Bruce M. Psaty, Weihong Tang, Charles Kooperberg, Kristian Hveem, Paul M. Ridker, Pierre Emmanuel Morange, Andrew D. Johnson, Christopher Kabrhel, David Alexandre Trégouët, Nicholas L. Smith, 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, Adam S. Butterworth, Caty Carrera, Cara L. Carty, Daniel I. Chasman, Wei Min Chen, John W. Cole, Adolfo Correa, Ioana 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, Stefan Gustafsson, Jeffrey Haessler, Tamara B. Harris, Ahamad Hassan, Aki S. Havulinna, Susan R. Heckbert, Elizabeth G. Holliday, George Howard, Fang Chi Hsu, Hyacinth I. Hyacinth, M. Arfan Ikram, Erik Ingelsson, Marguerite R. Irvin, Xueqiu Jian, Jordi Jiménez-Conde, Julie A. Johnson, J. Wouter Jukema, Masahiro Kanai, Keith L. Keene, Brett M. Kissela, Dawn O. Kleindorfer, Charles Kooperberg, 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 D. Mitchell, Thomas H. Mosley, Michael A. Nalls, Toshiharu Ninomiya, Martin J. O’Donnell, Bruce M. Psaty, Sara L. Pulit, Kristiina Rannikmäe, Alexander P. Reiner, Kathryn M. Rexrode, Kenneth Rice, Stephen S. Rich, Paul M. Ridker, Natalia S. Rost, Peter M. Rothwell, Jerome I. Rotter, 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, Kent D. Taylor, Vincent N.S. Thijs, Gudmar Thorleifsson, Unnur Thorsteinsdottir, Steffen Tiedt, Stella Trompet, Christophe Tzourio, Cornelia M. van Duijn, Matthew Walters, Nicholas J. Wareham, Sylvia Wassertheil-Smoller, James G. Wilson, Kerri L. Wiggins, Qiong Yang, Salim Yusuf, Najaf Amin, Hugo S. Aparicio, Donna K. 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, Atsushi Hozawa, Laura Ibanez, Andreea Ilinca, Martin Ingelsson, Motoki Iwasaki, Rebecca D. Jackson, 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, Christopher 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, Jose R. Romero, Jaume Roquer, 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, Andre 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 Pare, Jemma C. Hopewell, Danish Saleheen, Kari Stefansson, Bradford B. Worrall, Steven J. Kittner, Sudha Seshadri, Myriam Fornage, Hugh S. Markus, Joanna M.M. Howson, Yoichiro Kamatani, Stephanie Debette, Martin Dichgans

研究成果: ジャーナルへの寄稿学術誌査読

抄録

Background: 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. Objectives: 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 × 10−9 obtained after applying Bonferroni correction for the number of multi-trait combinations performed (n = 27). Results: 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. Conclusions: 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.

本文言語英語
ページ(範囲)1331-1349
ページ数19
ジャーナルJournal of Thrombosis and Haemostasis
20
6
DOI
出版ステータス出版済み - 6月 2022

!!!All Science Journal Classification (ASJC) codes

  • 血液学

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