TY - JOUR
T1 - Cross-Ancestry Investigation of Venous Thromboembolism Genomic Predictors
AU - Global Biobank Meta-Analysis Initiative; Estonian Biobank Research Team; 23andMe Research Team; Biobank Japan; CHARGE Hemostasis Working Group
AU - Thibord, Florian
AU - Klarin, Derek
AU - Brody, Jennifer A.
AU - Chen, Ming Huei
AU - Levin, Michael G.
AU - Chasman, Daniel I.
AU - Goode, Ellen L.
AU - Hveem, Kristian
AU - Teder-Laving, Maris
AU - Martinez-Perez, Angel
AU - Aïssi, Dylan
AU - Daian-Bacq, Delphine
AU - Ito, Kaoru
AU - Natarajan, Pradeep
AU - Lutsey, Pamela L.
AU - Nadkarni, Girish N.
AU - De Vries, Paul S.
AU - Cuellar-Partida, Gabriel
AU - Wolford, Brooke N.
AU - Pattee, Jack W.
AU - Kooperberg, Charles
AU - Braekkan, Sigrid K.
AU - Li-Gao, Ruifang
AU - Saut, Noemie
AU - Sept, Corriene
AU - Germain, Marine
AU - Judy, Renae L.
AU - Wiggins, Kerri L.
AU - Ko, Darae
AU - O'Donnell, Christopher J.
AU - Taylor, Kent D.
AU - Giulianini, Franco
AU - De Andrade, Mariza
AU - Nøst, Therese H.
AU - Boland, Anne
AU - Empana, Jean Philippe
AU - Koyama, Satoshi
AU - Gilliland, Thomas
AU - Do, Ron
AU - Huffman, Jennifer E.
AU - Wang, Xin
AU - Zhou, Wei
AU - Manuel Soria, Jose
AU - Carlos Souto, Juan
AU - Pankratz, Nathan
AU - Haessler, Jeffery
AU - Hindberg, Kristian
AU - Rosendaal, Frits R.
AU - Turman, Constance
AU - Olaso, Robert
N1 - Funding Information:
The INVENT Consortium is supported in part by National Heart, Lung, and Blood Institute grants HL134894 and HL154385 and by the GENMED Laboratory of Excellence on Medical Genomics ANR-10-LABX-0013, a research program managed by the National Research Agency (ANR) as part of the French Investment for the Future. This research is based on data from the Million Veteran Program, Office of Research and Development, Veterans Health Administration, and was supported by award MVP#003. The Analysis Commons was funded by the National Heart, Lung, and Blood Institute grant R01HL131136. Infrastructure for the CHARGE Consortium is supported in part by the National Heart, Lung, and Blood Institute grant R01HL105756. This work was supported by National Heart, Lung, and Blood Institute Intramural Research Program funding (F.T., M.-H.C., and A.D.J.). S.M.D. is supported by the Veterans Administration grant IK2-CX001780. Study-specific acknowledgments and funding can be found in the Supplemental Material .
Funding Information:
Dr Psaty serves on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. Dr Ridker has received investigator-initiated research grant support for unrelated projects from the National Heart, Lung, and Blood Institute, Operation Warp Speed, Novartis, Kowa, Amarin, and Pfizer; and has served as a consultant on unrelated issues to Novo Nordisk, Flame, Agepha, Uppton, Novartis, Jansen, Health Outlook, Civi Biopharm, Alnylam, and SOCAR. Dr Natarajan reports investigator-initiated grants from Amgen, Apple, AstraZeneca, Boston Scientific, and Novartis, and personal fees from Allelica, Apple, AstraZeneca, Blackstone Life Sciences, Foresite Labs, Novartis, and Roche/Genentech; is a co-founder of TenSixteen Bio; is a scientific advisory board member of Esperion Therapeutics, geneXwell, and TenSixteen Bio; and reports spousal employment at Vertex, all unrelated to the present work. Dr Chasman has received research funding for unrelated projects from Pfizer. Dr Ko initiated a research grant from Boston Scientific and received a consulting fee from Eagle Pharmaceutical, both unrelated to the current work. Dr O’Donnell is employed by Novartis Institute of Biomedical Research. Dr Cuellar-Partida and Dr Wang are employed by and hold stock or stock options in 23andMe, Inc. The spouse of Dr Willer works at Regeneron Pharmaceuticals. Dr Clapham reports fees from Tectonics Therapeutics. Dr Li-Gao is a contractor for Metabolon, Inc. Dr Do reports receiving grants from AstraZeneca, and grants and nonfinancial support from Goldfinch Bio; being a scientific co-founder, consultant, and equity holder for Pensieve Health (pending); and being a consultant for Variant Bio, all not related to this work. Dr Klarin is a scientific advisor and received consulting fees from Bitterroot Bio, Inc, unrelated to the current research. Dr Damrauer receives research support from RenalytixAI and personal consulting fees from Calico Labs, outside the scope of the current research. Dr Damrauer is named as a co-inventor on a government-owned US Patent application related to the use of genetic risk prediction for venous thromboembolic disease filed by the US Department of Veterans Affairs in accordance with federal regulatory requirements. The other authors report no conflicts.
Publisher Copyright:
© 2022 The Authors. Circulation is published on behalf of the American Heart Association, Inc., by Wolters Kluwer Health, Inc.
PY - 2022/10/18
Y1 - 2022/10/18
N2 - 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.
AB - 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.
KW - genetics
KW - genome-wide association study
KW - meta-analysis
KW - venous thromboembolism
KW - venous thrombosis
UR - http://www.scopus.com/inward/record.url?scp=85140273353&partnerID=8YFLogxK
U2 - 10.1161/CIRCULATIONAHA.122.059675
DO - 10.1161/CIRCULATIONAHA.122.059675
M3 - Article
C2 - 36154123
AN - SCOPUS:85140273353
VL - 146
SP - 1225
EP - 1242
JO - Circulation
JF - Circulation
SN - 0009-7322
IS - 16
ER -