Format

Send to

Choose Destination
Blood. 2019 Aug 16. pii: blood.2019000435. doi: 10.1182/blood.2019000435. [Epub ahead of print]

Genomic and Transcriptomic Association Studies Identify 16 Novel Susceptibility Loci for Venous Thromboembolism.

Author information

1
University of Washington, United States.
2
Environmental and Occupational Health Sciences, University of Washington, United States.
3
Pediatrics, University of California, San Diego, United States.
4
Pediatrics, University of Washington, United States.
5
Clinical Epidemiology, Leiden University Medical Center, Netherlands.
6
Health Sciences Research, Mayo Clinic, United States.
7
University of Minnesota, United States.
8
FHCRC, United States.
9
Norwegian University of Science and Technology, Norway.
10
Brigham and Women's Hospital, United States.
11
AP-HM, France.
12
Population Sciences Branch, National Heart, Lung, and Blood Institute, United States.
13
Harvard T.H. Chan School of Public Health, United States.
14
INSERM UMRS937, France.
15
Internal Medicine, University of Washington, United States.
16
Hematological Research Group, University of Tromsø, Norway.
17
Mayo Clinic.
18
The Ohio State University, United States.
19
Department of Public Health and Nursing, Norwegian University of Science and Technology, Norway.
20
Framingham Heart Study, United States.
21
APHM.
22
Corporal Michael Crescenz VA Medical Center, United States.
23
Medicine / Cardiology, Massachusetts General Hospital, United States.
24
Veteran's Administration, United States.
25
University of Texas Health Science Center at Houston, United States.
26
Unit Genomics of Complex Diseases, Institut d'Investigació Biomèdica Sant Pau, Spain.
27
Center for Population Genomics, MAVERIC, VA Boston Healthcare System, United States.
28
The Institute of Genomic Research, University of California, San Diego, United States.
29
Mayo Clinic, United States.
30
Institute for Translational Genomics and Popu, Los Angeles Biomedical Research Institute, United States.
31
Epidemiology and Community Health, University of Minnesota, United States.
32
Department of Epidemiology, University of Washington, United States.
33
Norwegian University of Science and Technology.
34
Centre National de Génotypage.
35
Epidemiology, Harvard T.H. Chan School of Public Health, United States.
36
Department of Clinical Medicine, UiT - The Arctic University of Norway, Norway.
37
Department of Clinical Epidemiology, Leiden University Medical Center, Netherlands.
38
Department of Hematology Research, Mayo Clinic, United States.
39
Department of Medicine, University of Washington, Seattle, WA, USA, United States.
40
Division of Preventive Medicine, Brigham and WOmen's Hospital, United States.
41
CHU Timone - Marseille France, France.
42
National Heart, Lung, and Blood Institute, The Framingham Heart Study, United States.
43
Emergency Medicine, Massachusetts General Hospital, Harvard Medical School, United States.
44
Unité Mixte de Recherche, S_1219, Institut National de la Santé et de la Recherche Médicale, France.
45
Department of Epidemiology, University of Washington, Seattle, WA 98101, USA., United States nlsmith@u.washington.edu.

Abstract

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. We meta-analyzed GWAS data from 18 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 both novel and previously known regions co-localized with eQTL 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.

PMID:
31420334
DOI:
10.1182/blood.2019000435

Supplemental Content

Full text links

Icon for HighWire
Loading ...
Support Center