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Get Free AccessBackgroundMulti‐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.ObjectivesTo discover novel genetic associations by combining summary data of correlated hemostatic traits and disease events.MethodsSummary 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).ResultsAcross 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.ConclusionsThe 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.
Gerard Temprano‐Sagrera, Colleen M. Sitlani, William P. Bone, Miguel Martín‐Bórnez, 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 D. Johnson, Anne Richmond, Annette Peters, Astrid van Hylckama Vlieg, Barbara McKnight, Bruce M. Psaty, Caroline Hayward, Cavin Ward‐Caviness, Christopher J. O’Donnell, Daniel I. Chasman, David P. Strachan, David‐Alexandre Trégouët, Dennis O. 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 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‐Emmanuel Morange, Pim van der Harst, Qiong Yang, Ngoc‐Quynh Le, Riccardo E. Marioni, Rui‐Fang Li, Scott M. Damrauer, Simon R. Cox, Stella Trompet, Stephan B. Felix, Uwe Völker, Weihong Tang, Wolfgang Köenig, J. Wouter Jukema, Xiuqing Guo, Sara Lindstrӧm, Lu Wang, Erin N. Smith, William Gordon, Astrid van Hylckama Vlieg, Mariza de Andrade, Jennifer A. Brody, Jack Pattee, Jeffrey Haessler, Ben Brumpton, Daniel I. Chasman, Pierre Suchon, Ming‐Huei Chen, Constance Turman, Marine Germain, Kerri L. Wiggins, James W. MacDonald, Sigrid K. Brækkan (2022). Multi‐phenotype analyses of hemostatic traits with cardiovascular events reveal novel genetic associations. Journal of Thrombosis and Haemostasis, 20(6), pp. 1331-1349, DOI: 10.1111/jth.15698.
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Type
Article
Year
2022
Authors
100
Datasets
0
Total Files
0
Language
English
Journal
Journal of Thrombosis and Haemostasis
DOI
10.1111/jth.15698
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