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 - 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
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U2 - 10.1161/CIRCULATIONAHA.122.059675
DO - 10.1161/CIRCULATIONAHA.122.059675
M3 - Article
C2 - 36154123
AN - SCOPUS:85140273353
SN - 0009-7322
VL - 146
SP - 1225
EP - 1242
JO - Circulation
JF - Circulation
IS - 16
ER -