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

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1331-1349
Number of pages19
JournalJournal of Thrombosis and Haemostasis
Volume20
Issue number6
DOIs
StatePublished - Jun 2022

Bibliographical note

Funding Information:
This study is supported in part by the National Heart, Lung, and Blood Institute grants HL134894, HL139553, and HL141291. The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute; the National Institutes of Health; the Department of Veterans Affairs; the United States Government or the US Department of Health and Human Services. G. Temprano-Sagrera is supported by the Pla Estratègic de Recerca i Innovació en Salut (PERIS) grant from the Catalan Department of Health for junior research personnel (SLT017/20/000100). S.M. Damrauer is supported by IK2-CX001780. M. Sabater-Lleal is supported by a Miguel Servet contract from the ISCIII Spanish Health Institute (CP17/00142) and co-financed by the European Social Fund. Data on coronary artery disease has been contributed by CARDIoGRAMplusC4D investigators and have been downloaded from www.CARDIOGRAMPLUSC4D.ORG. We thank the authors P. van der Harst and N. Verwejj who have made available the meta-analysis between CARDIoGRAMplusC4D and UK Biobank data on Mendeley (https://data.mendeley.com/datasets/gbbsrpx6bs/1). Part of the data used for this research was provided by M. Kubo and is available at the website of the National Bioscience Database Center (NBDC; https://humandbs.biosciencedbc.jp/en/hum0014-v21#cad) of the Japan Science and Technology Agency (JST). We also thank the MEGASTROKE consortium for making the IS data available at https://www.megastroke.org/. The MEGASTROKE project received funding from sources specified at http://www.megastroke.org/acknowledgments.html. Appendix A contains a list of investigators belonging to the CHARGE consortium Hemostasis Working Group that contributed to the hemostatic summary data. Appendix B contains a list of investigators from the INVENT consortium that contributed to the VTE summary data. Appendix C contains a list of investigators from the MEGASTROKE consortium that contributed to the IS summary data.

Funding Information:
This study is supported in part by the National Heart, Lung, and Blood Institute grants HL134894, HL139553, and HL141291. The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute; the National Institutes of Health; the Department of Veterans Affairs; the United States Government or the US Department of Health and Human Services. G. Temprano‐Sagrera is supported by the grant from the Catalan Department of Health for junior research personnel (SLT017/20/000100). S.M. Damrauer is supported by IK2‐CX001780. M. Sabater‐Lleal is supported by a contract from the ISCIII Spanish Health Institute (CP17/00142) and co‐financed by the European Social Fund. Pla Estratègic de Recerca i Innovació en Salut (PERIS) Miguel Servet

Publisher Copyright:
© 2022 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis.

Keywords

  • blood coagulation
  • cardiovascular diseases
  • genetic pleiotropy
  • genome-wide association study
  • hemostasis

PubMed: MeSH publication types

  • Journal Article

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