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Genomic and transcriptomic association studies identify 16 novel susceptibility loci for venous thromboembolism
Open accessAbstract
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 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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“Common genetic variants in PLCG2 also link the enzyme to type 1 diabetes (119) and venous thromboembolism (120), which could have a shared autoimmune etiology.”
From The role of PLCγ2 in immunological disorders, cancer, and neurodegeneration (2021) · cites this paper as [120]
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Metadata
- Authors
- Lindström, S., Wang, L., Smith, E. N., Gordon, W., van Hylckama Vlieg, A., de Andrade, M., Brody, J. A., Pattee, J. W., Haessler, J., Brumpton, B. M., Chasman, D. I., Suchon, P., Chen, M.-H., Turman, C., Germain, M., Wiggins, K. L., MacDonald, J., Braekkan, S. K., Armasu, S. M., Pankratz, N., Jackson, R. D., Nielsen, J. B., Giulianini, F., Puurunen, M. K., Ibrahim, M., Heckbert, S. R., Damrauer, S. M., Natarajan, P., Klarin, D., Program, T. M. V., de Vries, P. S., Sabater-Lleal, M., Huffman, J. E., The CHARGE Hemostasis Working Group, Bammler, T. K., Frazer, K. A., McCauley, B. M., Taylor, K., Pankow, J. S., Reiner, A. P., Gabrielsen, M. E., Deleuze, J.-F., O'Donnell, C. J., Kim, J., McKnight, B., Kraft, P., Hansen, J.-B., Rosendaal, F. R., Heit, J. A., Psaty, B. M., Tang, W., Kooperberg, C., Hveem, K., Ridker, P. M., Morange, P.-E., Johnson, A. D., Kabrhel, C., Trégouët, D.-A., & Smith, N. L.
- Affiliations
- University of Washington (US)
- University of California San Diego (US)
- Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands;
- Mayo Clinic (US)
- University of Minnesota (US)
- Fred Hutch Cancer Center (US)
- Norwegian University of Science and Technology (NO)
- Brigham and Women's Hospital (US)
- Inserm (FR)
- National Institutes of Health (US)
- Harvard University (US)
- Université de Bordeaux (FR)
- K.G. Jebsen Thrombosis Research and Expertise Center, Department of Clinical Medicine, UiT–The Arctic University of Norway, Tromsø, Norway;
- The Ohio State University (US)
- University of Michigan (US)
- Framingham Heart Study (US)
- Hôpital de la Timone (FR)
- Kaiser Permanente Washington Health Research Institute (US)
- Philadelphia VA Medical Center (US)
- Broad Institute (US)
- The University of Texas Health Science Center at Houston (US)
- Karolinska University Hospital (SE)
- Unit of Genomics of Complex Diseases, Institut de Recerca de l’Hospital de Sant Pau, IIB-Sant Pau, Barcelona, Spain;
- University of California, Los Angeles (US)
- Department of Epidemiology, University of Washington, Seattle, WA;
- University Hospital of North Norway (NO)
- United States Department of Veterans Affairs (US)
- ORCID
- Lindström, Sara
- Wang, Lu
- Smith, Erin N.
- de Andrade, Mariza
- Brody, Jennifer A.
- Pattee, Jack W.
- Brumpton, Ben M.
- Chasman, Daniel I.
- Suchon, Pierre
- Chen, Ming-Huei
- Turman, Constance
- Germain, Marine
- Wiggins, Kerri L.
- MacDonald, James
- Armasu, Sebastian M.
- Pankratz, Nathan
- Nielsen, Jonas B.
- Puurunen, Marja K.
- Heckbert, Susan R.
- Damrauer, Scott M.
- Natarajan, Pradeep
- Klarin, Derek
- de Vries, Paul S.
- Sabater-Lleal, Maria
- Huffman, Jennifer E.
- Bammler, Theo K.
- Frazer, Kelly A.
- McCauley, Bryan M.
- Taylor, Kent
- Pankow, James S.
- Gabrielsen, Maiken E.
- Deleuze, Jean-François
- Kim, Jihye
- Kraft, Peter
- Rosendaal, Frits R.
- Heit, John A.
- Psaty, Bruce M.
- Tang, Weihong
- Kooperberg, Charles
- Hveem, Kristian
- Ridker, Paul M.
- Morange, Pierre-Emmanuel
- Johnson, Andrew D.
- Kabrhel, Christopher
- Trégouët, David-Alexandre
- Smith, Nicholas L.
- Venue
- Blood
- Publisher
- American Society of Hematology
- Published
- 2019-08-16
- Volume
- 134
- Issue
- 19
- Pages
- 1645-1657
- ISSN
- 0006-4971 (ISSN-L)
- 1528-0020
- PMC
- PMC6871304
- OpenAlex
- W2968081931
- Cited by
- 223
- References
- 98
- Citations by year
- 2026: 15 · 2025: 31 · 2024: 34 · 2023: 45 · 2022: 38 · 2021: 38 · 2020: 18 · 2019: 4
- FWCI
- 14.77
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Blood (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- HAL (submittedVersion)
- Leiden Repository (Leiden University) (submittedVersion)
- Oskar-Bordeaux (Universite de Bordeaux) (submittedVersion)
- Funders
- U.S. Department of Health and Human Services
- Stiftelsen Kristian Gerhard Jebsen
- Agence Nationale de la Recherche (ANR-10-LABX-0013)
- National Institutes of Health (1r01hl120393-01a1, HL141791)
- National Heart, Lung, and Blood Institute (HL134894, R61HL141791, HL116854, R01-HL120393, R01HL134894, U01HL130114, HL141791, U01HL120393, HL139553, R01HL116854, R01HL059367, R01HL105756, R33HL141791, R01HL139553)
- National Cancer Institute (U01CA182913)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Health Sciences › Medicine › Hematology › Blood Coagulation and Thrombosis Mechanisms
- Health Sciences › Medicine › Internal Medicine › Venous Thromboembolism Diagnosis and Management
- Keywords
- venous thromboembolism, genetic susceptibility loci, transcriptome-wide association study, whole blood gene expression, hepatic gene expression, expression quantitative trait loci, Mendelian randomization, blood characteristics, pleckstrin, GRK5, PLCγ2, SMG6, eIF5A, SH2B3, ERAP1, thrombosis risk
- MeSH terms
- Humans, Genetic Predisposition to Disease, Venous Thromboembolism, Genome-Wide Association Study
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