Cross-Ancestry Investigation of Venous Thromboembolism Genomic Predictors - Archive ouverte HAL Access content directly
Journal Articles Circulation Year : 2022

Cross-Ancestry Investigation of Venous Thromboembolism Genomic Predictors

Florian Thibord , Derek Klarin , Jennifer A. Brody , Ming-Huei Chen , Michael G. Levin , Daniel I. Chasman , Ellen L. Goode , Kristian Hveem , Maris Teder-Laving , Angel Martinez-Perez , Dylan Aissi (1) , Delphine Daian-Bacq , Kaoru Ito , Pradeep Natarajan , Pamela L. Lutsey , Girish N. Nadkarni , Paul S. de Vries , Gabriel Cuellar-Partida , Brooke N. Wolford , Jack W. Pattee , Charles Kooperberg , Sigrid K. Braekkan , Ruifang Li-Gao , Noemie Saut (2) , Corriene Sept , Marine Germain (1) , Renae L. Judy , Kerri L. Wiggins , Darae Ko , Christopher J. O'Donnell , Kent D. Taylor , Franco Giulianini , Mariza de Andrade , Therese H. Nost , Anne Boland , Jean-Philippe Empana (3) , Satoshi Koyama , Thomas Gilliland , Ron Do , Jennifer E. Huffman , Xin Wang , Wei Zhou , Jose Manuel Soria , Juan Carlos Souto , Nathan Pankratz , Jeffery Haessler , Kristian Hindberg , Frits R. Rosendaal , Constance Turman , Robert Olaso , Rachel L. Kember , Traci M. Bartz , Julie A. Lynch , Susan R. Heckbert , Sebastian M. Armasu , Ben Brumpton , David M. Smadja (4) , Xavier Jouven (3) , Issei Komuro , Katharine R. Clapham , Ruth J. F. Loos , Cristen J. Willer , Maria Sabater-Lleal , James S. Pankow , Alexander P. Reiner , Vania M. Morelli , Paul M. Ridker , Astrid van Hylckama Vlieg , Jean-Francois Deleuze , Peter Kraft , Daniel J. Rader , Kyung Min Lee , Bruce M. Psaty , Anne Heidi Skogholt , Joseph Emmerich (5) , Pierre Suchon , Stephen S. Rich , Ha My T Vy , Weihong Tang , Rebecca D. Jackson , John-Bjarne Hansen , Pierre-Emmanuel Morange (2) , Christopher Kabrhel , David-Alexandre Tregouet (1) , Scott M. Damrauer , Andrew D. Johnson , Nicholas L. Smith
Florian Thibord
  • Function : Author
Derek Klarin
  • Function : Author
Jennifer A. Brody
  • Function : Author
Ming-Huei Chen
  • Function : Author
Michael G. Levin
  • Function : Author
Daniel I. Chasman
  • Function : Author
Ellen L. Goode
  • Function : Author
Kristian Hveem
  • Function : Author
Maris Teder-Laving
  • Function : Author
Angel Martinez-Perez
  • Function : Author
Delphine Daian-Bacq
  • Function : Author
Kaoru Ito
  • Function : Author
Pradeep Natarajan
  • Function : Author
Pamela L. Lutsey
  • Function : Author
Girish N. Nadkarni
  • Function : Author
Paul S. de Vries
  • Function : Author
Gabriel Cuellar-Partida
  • Function : Author
Brooke N. Wolford
  • Function : Author
Jack W. Pattee
  • Function : Author
Charles Kooperberg
  • Function : Author
Sigrid K. Braekkan
  • Function : Author
Ruifang Li-Gao
  • Function : Author
Corriene Sept
  • Function : Author
Renae L. Judy
  • Function : Author
Kerri L. Wiggins
  • Function : Author
Darae Ko
  • Function : Author
Christopher J. O'Donnell
  • Function : Author
Kent D. Taylor
  • Function : Author
Franco Giulianini
  • Function : Author
Mariza de Andrade
  • Function : Author
Therese H. Nost
  • Function : Author
Anne Boland
  • Function : Author
Satoshi Koyama
  • Function : Author
Thomas Gilliland
  • Function : Author
Ron Do
  • Function : Author
Jennifer E. Huffman
  • Function : Author
Xin Wang
  • Function : Author
Wei Zhou
  • Function : Author
Jose Manuel Soria
  • Function : Author
Juan Carlos Souto
  • Function : Author
Nathan Pankratz
  • Function : Author
Jeffery Haessler
  • Function : Author
Kristian Hindberg
  • Function : Author
Frits R. Rosendaal
  • Function : Author
Constance Turman
  • Function : Author
Robert Olaso
  • Function : Author
Rachel L. Kember
  • Function : Author
Traci M. Bartz
  • Function : Author
Julie A. Lynch
  • Function : Author
Susan R. Heckbert
  • Function : Author
Sebastian M. Armasu
  • Function : Author
Ben Brumpton
  • Function : Author
Issei Komuro
  • Function : Author
Katharine R. Clapham
  • Function : Author
Ruth J. F. Loos
  • Function : Author
Cristen J. Willer
  • Function : Author
Maria Sabater-Lleal
  • Function : Author
James S. Pankow
  • Function : Author
Alexander P. Reiner
  • Function : Author
Vania M. Morelli
  • Function : Author
Paul M. Ridker
  • Function : Author
Astrid van Hylckama Vlieg
  • Function : Author
Jean-Francois Deleuze
  • Function : Author
Peter Kraft
  • Function : Author
Daniel J. Rader
  • Function : Author
Kyung Min Lee
  • Function : Author
Bruce M. Psaty
  • Function : Author
Anne Heidi Skogholt
  • Function : Author
Pierre Suchon
  • Function : Author
Stephen S. Rich
  • Function : Author
Ha My T Vy
  • Function : Author
Weihong Tang
  • Function : Author
Rebecca D. Jackson
  • Function : Author
John-Bjarne Hansen
  • Function : Author
Christopher Kabrhel
  • Function : Author
Scott M. Damrauer
  • Function : Author
Andrew D. Johnson
  • Function : Author
Nicholas L. Smith
  • Function : Author

Abstract

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.
Fichier principal
Vignette du fichier
article.pdf (5.56 Mo) Télécharger le fichier
Origin Files produced by the author(s)

Dates and versions

hal-03836618 , version 1 (18-06-2024)

Identifiers

Cite

Florian Thibord, Derek Klarin, Jennifer A. Brody, Ming-Huei Chen, Michael G. Levin, et al.. Cross-Ancestry Investigation of Venous Thromboembolism Genomic Predictors. Circulation, 2022, 146 (16), ⟨10.1161/CIRCULATIONAHA.122.059675⟩. ⟨hal-03836618⟩
64 View
4 Download

Altmetric

Share

Gmail Mastodon Facebook X LinkedIn More