Cross-Ancestry Investigation of Venous Thromboembolism Genomic Predictors
2022
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 | Aissi, 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 | Nost, 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-Francois | Kraft, Peter | Rader, Daniel J. | 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 | Tregouet, David-Alexandre | Damrauer, Scott M. | Johnson, Andrew D. | Smith, Nicholas L. | Bordeaux population health (BPH) ; Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM) | Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN) ; Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE) | Paris-Centre de Recherche Cardiovasculaire (PARCC (UMR_S 970/ U970)) ; Hôpital Européen Georges Pompidou [APHP] (HEGP) ; Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité) | Innovations thérapeutiques en hémostase = Innovative Therapies in Haemostasis (IThEM - U1140) ; Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité) | Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)) ; Conservatoire National des Arts et Métiers [CNAM] (CNAM) ; HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)
International audience
Mostrar más [+] Menos [-]Inglés. 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 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.
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