Cross-Ancestry Investigation of Venous Thromboembolism Genomic Predictors
Authors: Thibord Florian , Klarin Derek , Brody Jennifer A. , Chen Ming-Huei , Levin Michael G. , Chasman Daniel I. , Goode Ellen L. , Hveem Kristian , Teder-Laving Maris , Martinez-Perez Angel , Aïssi Dylan , Daian-Bacq Delphine , Ito Kaoru , Natarajan Pradeep , Lutsey Pamela L. , Nadkarni Girish N. , Cuellar-Partida Gabriel , Wolford Brooke N. , Pattee Jack W. , Kooperberg Charles , Braekkan Sigrid K. , Li-Gao Ruifang , Saut Noemie , Sept Corriene , Germain Marine , Judy Renae L. , Wiggins Kerri L. , Ko Darae , O’Donnell Christopher , Taylor Kent D. , Giulianini Franco , De Andrade Mariza , Nøst Therese H. , Boland Anne , Empana Jean-Philippe , Koyama Satoshi , Gilliland Thomas , Do Ron , Wang Xin , Zhou Wei , Soria Jose Manuel , Souto Juan Carlos , Pankratz Nathan , Haessler Jeffery , Hindberg Kristian , Rosendaal Frits R. , Turman Constance , Olaso Robert , Kember Rachel L. , Bartz Traci M. , Lynch Julie A. , Heckbert Susan R. , Armasu Sebastian M. , Brumpton Ben , Smadja David M. , Jouven Xavier , Komuro Issei , Clapham Katharine , Loos Ruth J.F. , Willer Cristen , Sabater-Lleal Maria , Pankow James S. , Reiner Alexander P. , Morelli Vania M. , Ridker Paul M. , van Hylckama Vlieg Astrid , Deleuze Jean-François , Kraft Peter , Rader Daniel J. , McKnight Barbara ,   Global Biobank Meta-Analysis Initiative,   Estonian Biobank Research Team,   23andMe Research Team, Lee Kyung Min , Psaty Bruce M. , Skogholt Anne Heidi , Emmerich Joseph , Suchon Pierre , Japan Biobank , Rich Stephen S. , Vy Ha My T. , Tang Weihong , Jackson Rebecca D. , Hansen John-Bjarne , Morange Pierre-Emmanuel , Kabrhel Christopher , Trégouët David-Alexandre , Damrauer Scott , Johnson Andrew D. , Smith Nicholas L. 
Published: March 2022

ABSTRACTVenous thromboembolism (VTE) is a complex disease with environmental and genetic determinants. We present new cross-ancestry meta-analyzed genome-wide association study (GWAS) results from 30 studies, with replication of novel loci and their characterization throughin silicogenomic interrogations. In our initial genetic discovery effort that included 55,330 participants with VTE (47,822 European, 6,320 African, and 1,188 Hispanic ancestry), we identified 48 novel associations of which 34 replicated after correction for multiple testing. In our combined discovery-replication analysis (81,669 VTE participants) and ancestry-stratified meta-analyses (European, African and Hispanic), we identified another 44 novel associations, which are new candidate VTE-associated loci requiring replication. In total, across all GWAS meta-analyses, we identified 135 independent genomic loci significantly associated with VTE risk. We also identified 31 novel transcript associations in transcriptome-wide association studies and 8 novel candidate genes with protein QTL Mendelian randomization analyses.In silicointerrogations of hemostasis and hematology traits and a large phenome-wide association analysis of the 135 novel GWAS loci provided insights to biological pathways contributing to VTE, indicating that some loci may contribute to VTE through well-characterized coagulation pathways while others provide new data on the role of hematology traits, particularly platelet function. Many of the replicated loci are outside of known or currently hypothesized pathways to thrombosis. In summary, these findings highlight new pathways to thrombosis and provide novel molecules that may be useful in the development of antithrombosis treatments with reduced risk of bleeds.