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. , de Vries Paul S. , 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 J. , Taylor Kent D. , Giulianini Franco , De Andrade Mariza , Nøst Therese H. , Boland Anne , Empana Jean-Philippe , Koyama Satoshi , Gilliland Thomas , Do Ron , Huffman Jennifer E. , Wang Xin , Zhou Wei , Manuel Soria Jose , Carlos Souto Juan , 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 R. , Loos Ruth J.F. , Willer Cristen J. , Sabater-Lleal Maria , Pankow James S. , Reiner Alexander P. , Morelli Vania M. , Ridker Paul M , Vlieg Astrid van Hylckama , Deleuze Jean-François , Kraft Peter , Rader Daniel J. ,   Global Biobank Meta-Analysis Initiative; Estonian Biobank Research Team; 23andMe Research Team; Biobank Japan; CHARGE Hemostasis Working Group, Min Lee Kyung , Psaty Bruce M. , Heidi Skogholt Anne , Emmerich Joseph , Suchon Pierre , 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 M. , Johnson Andrew D. , Smith Nicholas L. 
Published: October 2022

Background:
Venous thromboembolism (VTE) is a life-threatening vascular event with environmental and genetic determinants. Recent VTE genome-wide association studies (GWAS) meta-analyses involved nearly 30 000 VTE cases and identified up to 40 genetic loci associated with VTE risk, including loci not previously suspected to play a role in hemostasis. The aim of our research was to expand discovery of new genetic loci associated with VTE by using cross-ancestry genomic resources.

Methods:
We present new cross-ancestry meta-analyzed GWAS results involving up to 81 669 VTE cases from 30 studies, with replication of novel loci in independent populations and loci characterization through in silico genomic interrogations.

Results:
In our genetic discovery effort that included 55 330 participants with VTE (47 822 European, 6320 African, and 1188 Hispanic ancestry), we identified 48 novel associations, of which 34 were 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. A genetic risk score of the significantly associated loci in Europeans identified a 6-fold increase in risk for those in the top 1% of scores compared with those with average scores. We also identified 31 novel transcript associations in transcriptome-wide association studies and 8 novel candidate genes with protein quantitative-trait locus Mendelian randomization analyses. In silico interrogations of hemostasis and hematology traits and a large phenome-wide association analysis of the 135 GWAS loci provided insights to biological pathways contributing to VTE, with some loci contributing to VTE through well-characterized coagulation pathways and others providing 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.

Conclusions:
Our cross-ancestry GWAS meta-analyses identified new loci associated with VTE. These findings highlight new pathways to thrombosis and provide novel molecules that may be useful in the development of improved antithrombosis treatments.