OC 56.1 - A Cross-Ancestry Meta-Analysis of Venous Thromboembolism Genetic Associations

Tuesday, July 12, 2022

10:45 AM – 11:00 AM

Location: ExCel Center, ICC Capital Suite Room 10&11

Presentation Format: In-Person

Presenting Author(s)

FT

Florian Thibord, PhD

Post-Doctoral researcher
Population Sciences Branch, Division of Intramural Research, National Heart, Lung and Blood Institute, Framingham, MA, USA.
Framingham, Massachusetts, United States

Co-Author(s)

DK

Derek Klarin

Assistant Professor
Division of Vascular Surgery, Stanford University School of Medicine
Palo Alto, California, United States
DC

Daniel Chasman

Associate Professor
Division of Preventive Medicine, Brigham and Women's Hospital
Boston, Massachusetts, United States
MT

Maris Teder-Laving

Research Fellow
Institute of Genomics, University of Tartu
Tartu, Tartumaa, Estonia
EG

Ellen Goode

Professor
Department of Quantitative Health Sciences, Mayo Clinic
Rochester, Minnesota, United States
KH

Kristian Hveem

Professor
HUNT Research Center, Department of Public Health and Nursing, Norwegian University of Science and Technology
Levanger, Sor-Trondelag, Norway
AM

Angel Martinez-Perez

Research Associate
Genomics of Complex Diseases Group, Research Institute Hospital de la Santa Creu i Sant Pau, IIB Sant Pau
Barcelona, Catalonia, Spain
JE

Joseph Emmerich

Professor
Department of vascular medicine, Paris Saint-Joseph Hospital Group, University of Paris
Paris, Ile-de-France, France
XJ

Xavier Jouven

Professor
Department of Epidemiology, Université Paris Descartes, Sorbonne Paris Cité
Paris, Ile-de-France, France
KI

Kaoru Ito

Principal Investigator
Laboratory for Cardiovascular Genomics and Informatics, RIKEN Center for Integrative Medical Sciences
Yokohama, Kanagawa, Japan
GC

Gabriel Cuellar Partida

Scientist I, Statistical Genetics
23andMe, Inc.
Sunnyvale, California, United States
JH

Jeffrey Haessler

Research Associate
Division of Public Health Sciences, Fred Hutchinson Cancer Research Center
Seattle, Washington, United States
JH

John-Bjarne Hansen, MD, PhD

Professor
Thrombosis Research Center (TREC), Division of Internal Medicine, University Hospital of North Norway, Tromsø, Norway
Tromsø, Troms, Norway
Av

Astrid van Hylckama Vlieg, PhD

Assistant Professor
Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands
Leiden, Zuid-Holland, Netherlands
PM

Pierre-Emmanuel Morange, MD, PhD

MD, PhD
Aix-Marseille Univ, INSERM, INRAE, C2VN, Laboratory of Haematology, Hôpitaux de Marseille, Marseille, France
Marseille, Provence-Alpes-Cote d'Azur, France
CK

Christopher Kabrhel

Professor
Emergency Medicine, Massachusetts General Hospital
Boston, Massachusetts, United States
David-Alexandre TREGOUET, PhD

Senior Investigator
Bordeaux Population Health research center - INSERM UMR1219
Bordeaux, Aquitaine, France
SD

Scott Damrauer

Assistant Professor
Corporal Michael J. Crescenz VA Medical Center
Philadelphia, Pennsylvania, United States
Andrew D. D. Johnson, PhD

Professor
Population Sciences Branch, Division of Intramural Research, National Heart, Lung and Blood Institute, Framingham, MA, USA.
Framingham, Massachusetts, United States
NS

Nicholas L. Smith

Professor, Epidemiology
Department of Epidemiology, School of Public Health, University of Washington
Seattle, Washington, United States

Background: Venous thromboembolism (VTE) is a cardiovascular event that manifests as deep vein thrombosis or pulmonary embolism. Over the last decade, genetic association studies uncovered up to 40 genetic loci associated with VTE risk.

Aims: To discover novel gene loci influencing VTE risk and extend our understanding of the genetic architecture of VTE, we conducted an expanded meta-analysis of VTE genome wide association studies (GWAS).

Methods: We meta-analyzed GWAS results from 14 studies, which included 81,669 VTE cases and over a million controls from European, African, Hispanic, East and South-Asian ancestries. We first conducted a cross-ancestry discovery meta-analysis using a subset of 4 studies (N=55,330 cases), while the remaining studies were reserved to replicate discovery loci that exceeded the significance threshold (P < 5x10-8). The discovery and replication studies were then meta-analyzed to create a combined, cross-ancestry dataset along with Europeans and Africans ancestry-specific meta-analyses. Subsequent analyses included fine-mapping, transcriptome and proteome-wide association analyses.

Results: The discovery meta-analysis revealed 85 genome-wide significant loci, including 48 mapping to gene loci that were not previously reported for VTE. In the replication study, 46 out of the 48 novel loci had a concordant effect direction with the discovery analysis, of which 34 passed the Bonferroni-corrected significance threshold, including 3 involving variants with low frequency and large effect sizes: ST3GAL4 (frequency=0.021, OR=1.19), ZMIZ1 (frequency=0.029, OR=1.12) and MAP1A (frequency=0.027, OR=0.85). The combined and ancestry-stratified meta-analyses established an additional 46 novel signals reaching genome-wide significance. Conditional analyses revealed secondary signals at 20 loci, while proteome and transcriptome analyses identified putative genes at novel loci (e.g. TIMP3, TIMP4 and NFE2). VTE variants discovered with these analyses were mostly associated with blood traits, and platelet traits in particular.

Conclusion(s): This work substantially increases the known VTE genetic loci, unveiling new insights on the etiology of the disease and potential opportunities for new targeted treatments.