Genomic and transcriptomic association studies identify 16 novel susceptibility loci for venous thromboembolism

Sara Lindstrom; Lu Wang; Erin N. Smith; William Gordon; Astrid van Hylckama Vlieg; Mariza de Andrade; Jennifer A. Brody; Jack W. Pattee; Jeffrey Haessler; Ben M. Brumpton; Daniel I. Chasman; Pierre Suchon; Ming-Huei Chen; Constance Turman; Marine Germain; Kerri L. Wiggins; James MacDonald; Sigrid K. Braekkan; Sebastian M. Armasu; Nathan Pankratz; Rebecca D. Jackson; Jonas B. Nielsen; Franco Giulianini; Marja K. Puurunen; Manal Ibrahim; Susan R. Heckbert; Scott M. Damrauer; Pradeep Natarajan; Derek Klarin; Paul S. de Vries; Maria Sabater-Lleal; Jennifer E. Huffman; Theo K. Bammler; Kelly A. Frazer; Bryan M. McCauley; Kent Taylor; James S. Pankow; Alexander P. Reiner; Maiken E. Gabrielsen; Jean-Francois Deleuze; Chris J. O'Donnell; Jihye Kim; Barbara McKnight; Peter Kraft; John-Bjarne Hansen; Frits R. Rosendaal; John A. Heit; Bruce M. Psaty; Weihong Tang; Charles Kooperberg; Kristian Hveem; Paul M. Ridker; Pierre-Emmanuel Morange; Andrew D. Johnson; Christopher Kabrhel; David-Alexandre Tregouet; Nicholas L. Smith; Emma Busenkell; Renae Judy; Julie Lynch; Michael Levin; J. H. Krishna Aragam; Mark Chaffin; Mary Haas; Themistocles L. Assimes; Jie Huang; Kyung Min Lee; Qing Shao; C. Kabrhel; Yunfeng Huang; Yan V. Sun; Marijana Vujkovic; Danish Saleheen; Donald R. Miller; Peter Reaven; Scott DuVall; William Boden; Saiju Pyarajan; Peter Henke; C. Kooperberg; J. Michael Gaziano; John Concato; Daniel J. Rader; Kelly Cho; Kyong-Mi Chang; Peter W. F. Wilson; Philip S. Tsao; Sekar Kathiresan; Andrea Obi; INVENT Consortium

doi:10.1182/blood.2019000435

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Genomic and transcriptomic association studies identify 16 novel susceptibility loci for venous thromboembolism

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Genomic and transcriptomic association studies identify 16 novel susceptibility loci for venous thromboembolism

Sara Lindstrom, Lu Wang, Erin N. Smith, William Gordon, Astrid van Hylckama Vlieg, Mariza de Andrade, Jennifer A. Brody, Jack W. Pattee, Jeffrey Haessler, Ben M. Brumpton, …

Blood, Vol.134(19), pp.1645-1657

07/11/2019

DOI: https://doi.org/10.1182/blood.2019000435

PMID: 31420334

Abstract

Hematology

Life Sciences & Biomedicine

Science & Technology

Venous thromboembolism (VTE) is a significant contributor to morbidity and mortality. To advance our understanding of the biology contributing to VTE, we conducted a genome-wide association study (GWAS) of VTE and a transcriptome-wide association study (TWAS) based on imputed gene expression from whole blood and liver. Wemeta-analyzedGWAS data from18 studies for 30 234 VTE cases and 172 122 controls and assessed the association between 12 923 718 genetic variants and VTE. We generated variant prediction scores of gene expression from whole blood and liver tissue and assessed them for association with VTE. Mendelian randomization analyses were conducted for traits genetically associated with novel VTE loci. We identified 34 independent genetic signals for VTE risk from GWAS meta-analysis, of which 14 are newly reported associations. This included 11 newly associated genetic loci (C1orf198, PLEK, OSMR-AS1, NUGGC/SCARA5, GRK5, MPHOSPH9, ARID4A, PLCG2, SMG6, EIF5A, and STX10) of which 6 replicated, and 3 new independent signals in 3 known genes. Further, TWAS identified 5 additional genetic loci with imputed gene expression levels differing between cases and controls in whole blood (SH2B3, SPSB1, RP11-747H7.3, RP4-737E23.2) and in liver (ERAP1). At some GWAS loci, we found suggestive evidence that the VTE association signal for novel and previously known regions colocalized with expression quantitative trait locus signals. Mendelian randomization analyses suggested that blood traits may contribute to the underlying risk of VTE. To conclude, we identified 16 novel susceptibility loci for VTE; for some loci, the association signals are likely mediated through gene expression of nearby genes.

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Title: Genomic and transcriptomic association studies identify 16 novel susceptibility loci for venous thromboembolism
Creators - without role: Sara Lindstrom - University of Washington
Lu Wang - University of Washington
Erin N. Smith - Univ Calif San Diego, Dept Pediat, La Jolla, CA 92093 USA
William Gordon - University of Washington
Astrid van Hylckama Vlieg - Leiden University
Mariza de Andrade - Mayo Clin, Dept Hlth Sci Res, Rochester, MN USA
Jennifer A. Brody - University of Washington
Jack W. Pattee - University of Minnesota
Jeffrey Haessler - Hutchinson
Ben M. Brumpton - Norwegian Univ Sci & Technol, NTNU, Dept Publ Hlth & Nursing, KG Jebsen Ctr Genet Epidemiol, Trondheim, Norway
Daniel I. Chasman - Brigham and Women's Hospital
Pierre Suchon - La Timone Hosp, Lab Haematol, Marseille, France
Ming-Huei Chen - NHLBI, Populat Sci Branch, NIH, Framingham, MA USA
Constance Turman - Supreme Council Of Health
Marine Germain - University of Bordeaux
Kerri L. Wiggins - University of Washington
James MacDonald - University of Washington
Sigrid K. Braekkan - UiT The Arctic University of Norway
Sebastian M. Armasu - Mayo Clin, Dept Hlth Sci Res, Rochester, MN USA
Nathan Pankratz - University of Minnesota
Rebecca D. Jackson - The Ohio State University
Jonas B. Nielsen - Supreme Council Of Health
Franco Giulianini - Brigham and Women's Hospital
Marja K. Puurunen - Framingham Heart Dis Epidemiol Study, Framingham, MA USA
Manal Ibrahim - La Timone Hosp, Lab Haematol, Marseille, France
Susan R. Heckbert - University of Washington
Scott M. Damrauer - College Station Medical Center
Pradeep Natarajan - Boston VA Healthcare Syst, Boston, MA USA
Derek Klarin - Boston VA Healthcare Syst, Boston, MA USA
Paul S. de Vries - Supreme Council Of Health
Maria Sabater-Lleal - IIB St Pau, Inst Recerca Hosp St Pau, Unit Genom Complex Dis, Barcelona, Spain
Jennifer E. Huffman - VA Boston Healthcare Syst, MAVERIC, Ctr Populat Genom, Boston, MA USA
Theo K. Bammler - University of Washington
Kelly A. Frazer - Univ Calif San Diego, Dept Pediat, La Jolla, CA 92093 USA
Bryan M. McCauley - Mayo Clin, Dept Hlth Sci Res, Rochester, MN USA
Kent Taylor - Biomed Research Institute
James S. Pankow - University of Minnesota
Alexander P. Reiner - University of Washington
Maiken E. Gabrielsen - Norwegian Univ Sci & Technol, NTNU, Dept Publ Hlth & Nursing, KG Jebsen Ctr Genet Epidemiol, Trondheim, Norway
Jean-Francois Deleuze - Evry
Chris J. O'Donnell - NHLBI, Populat Sci Branch, NIH, Framingham, MA USA
Jihye Kim - Supreme Council Of Health
Barbara McKnight - Hutchinson
Peter Kraft - Supreme Council Of Health
John-Bjarne Hansen - UiT The Arctic University of Norway
Frits R. Rosendaal - Leiden University
John A. Heit - Mayo Clin, Dept Hlth Sci Res, Rochester, MN USA
Bruce M. Psaty - Kaiser Permanente
Weihong Tang - University of Minnesota
Charles Kooperberg - Hutchinson
Kristian Hveem - Norwegian Univ Sci & Technol, NTNU, Dept Publ Hlth & Nursing, KG Jebsen Ctr Genet Epidemiol, Trondheim, Norway
Paul M. Ridker - Brigham and Women's Hospital
Pierre-Emmanuel Morange - La Timone Hosp, Lab Haematol, Marseille, France
Andrew D. Johnson - NHLBI, Populat Sci Branch, NIH, Framingham, MA USA
Christopher Kabrhel - College Station Medical Center
David-Alexandre Tregouet - University of Bordeaux
Nicholas L. Smith - University of Washington
Emma Busenkell
Renae Judy
Julie Lynch
Michael Levin
J. H. Krishna Aragam
Mark Chaffin
Mary Haas
Themistocles L. Assimes
Jie Huang
Kyung Min Lee
Qing Shao
C. Kabrhel
Yunfeng Huang
Yan V. Sun
Marijana Vujkovic
Danish Saleheen
Donald R. Miller
Peter Reaven
Scott DuVall
William Boden
Saiju Pyarajan
Peter Henke
C. Kooperberg
J. Michael Gaziano
John Concato
Daniel J. Rader
Kelly Cho
Kyong-Mi Chang
Peter W. F. Wilson
Philip S. Tsao
Sekar Kathiresan
Andrea Obi
INVENT Consortium
Publication Details: Blood, Vol.134(19), pp.1645-1657
Publisher: Amer Soc Hematology
Number of pages: 13
Grant note: HL116854 / Stiftelsen Kristian Gerhard Jebsen HL134894; HL139553; HL141791 / National Institutes of Health, National Heart, Lung, and Blood Institute; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Heart Lung & Blood Institute (NHLBI) R01HL148050 / NATIONAL HEART, LUNG, AND BLOOD INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Heart Lung & Blood Institute (NHLBI)
Identifiers: 9937864808331
Academic Unit: King Abdulaziz University
Language: English
Resource Type: Journal article