Multipopulation GWAS for venous thromboembolism identifies novel loci followed by experimental validation in zebrafish

Venous thromboembolisms (VTEs) are a leading cause of morbidity and mortality. Although many genetic risk factors have been identified, a substantial portion of the heritability remains unexplained. In this study, we employed a genome-wide association study (GWAS) for VTE across 9 international cohorts of the Global Biobank Meta-Analysis Initiative to address this question, along with in vivo functional validation. In this multipopulation GWAS (VTE cases, 27 987; controls, 1 035 290), 38 genome-wide significant loci were identified, 4 of which were potentially novel. For each autosomal locus, we performed gene prioritization using 7 independent, yet converging, lines of evidence. Through prioritization, we identified genes associated with VTE through GWAS and/or functional studies (eg, F5, F11, VWF, STAB2, PLCG2, TC2N), functionally validated those that did not have evidence other than GWAS (TC2N, TSPAN15), and discovered 1 not previously associated with coagulation (RASIP1). We evaluated the function of 6 prioritized genes with strong genetic evidence, including F7 as a positive control, using laser-mediated endothelial injury to induce thrombosis in zebrafish after CRISPR/Cas9 knockdown. From this assay, we have supportive evidence for the role of RASIP1 and TC2N in the modification of human VTE and suggestive evidence for STAB2 and TSPAN15. This study expands on the currently identified genomic architecture of VTE through biobank-based, multipopulation GWASs, in silico candidate gene predictions, and in vivo functional follow-up of candidate genes.

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Journal
Blood Advances
Published
2025-06-24
DOI
https://doi.org/10.1182/bloodadvances.2024015790
Primary Topic
Genetic Associations and Epidemiology
Type
article
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Multipopulation GWAS for venous thromboembolism identifies novel loci followed by experimental validation in zebrafish

Laxmi Bhatta, Catherine E. Richter, Benjamin M. Neale, Xinge Yu et al.
Blood Advances
Genetic Associations and Epidemiology
article

Multipopulation GWAS for venous thromboembolism identifies novel loci followed by experimental validation in zebrafish

Laxmi Bhatta, Catherine E. Richter, Benjamin M. Neale, Xinge Yu, Jordan A. Shavit, Karl C. Desch, Ida Surakka, Florian Thibord, Derek Klarin, Valeria Lo Faro, Kuan-Han H. Wu, Andrew D. Johnson, Cristen J. Willer, David‐Alexandre Trégouët, Ben Michael Brumpton, Scott M. Damrauer, Kristin Tsuo, Wei Zhou, Brooke N. Wolford, Nicholas L. Smith, Yakun Zhao, Mark J. Daly
article en

Abstract

Venous thromboembolisms (VTEs) are a leading cause of morbidity and mortality. Although many genetic risk factors have been identified, a substantial portion of the heritability remains unexplained. In this study, we employed a genome-wide association study (GWAS) for VTE across 9 international cohorts of the Global Biobank Meta-Analysis Initiative to address this question, along with in vivo functional validation. In this multipopulation GWAS (VTE cases, 27 987; controls, 1 035 290), 38 genome-wide significant loci were identified, 4 of which were potentially novel. For each autosomal locus, we performed gene prioritization using 7 independent, yet converging, lines of evidence. Through prioritization, we identified genes associated with VTE through GWAS and/or functional studies (eg, F5, F11, VWF, STAB2, PLCG2, TC2N), functionally validated those that did not have evidence other than GWAS (TC2N, TSPAN15), and discovered 1 not previously associated with coagulation (RASIP1). We evaluated the function of 6 prioritized genes with strong genetic evidence, including F7 as a positive control, using laser-mediated endothelial injury to induce thrombosis in zebrafish after CRISPR/Cas9 knockdown. From this assay, we have supportive evidence for the role of RASIP1 and TC2N in the modification of human VTE and suggestive evidence for STAB2 and TSPAN15. This study expands on the currently identified genomic architecture of VTE through biobank-based, multipopulation GWASs, in silico candidate gene predictions, and in vivo functional follow-up of candidate genes.

Blood AdvancesVol. 9(19)
Broad Institute (US), University Medical Center Groningen (NL), Kaiser Permanente Washington Health Research Institute (US), Université de Bordeaux (FR), Inserm (FR), Palo Alto University (US), University of Washington (US), Norwegian University of Science and Technology (NO), University of Michigan (US), Science for Life Laboratory (SE), VA Office of Research and Development (US), Massachusetts General Hospital (US), St Olav's University Hospital (NO), Bordeaux Population Health (FR), National Heart, Lung, and Blood Institute (US), Michigan United (US), Michigan Medicine (US), Framingham Heart Study (US), Philadelphia VA Medical Center (US), Institute for Molecular Medicine Finland (FI), Amsterdam University Medical Centers (NL), University of Pennsylvania (US), University of Amsterdam (NL), University of Toledo (US)
U.S. Department of Health and Human Services, U.S. Department of Veterans Affairs, Office of Research and Development, Taiwan Biobank, Norges Teknisk-Naturvitenskapelige Universitet, QIMR Berghofer Medical Research Institute, Agence Nationale de la Recherche, Université de Bordeaux, St. Olavs Hospital Universitetssykehuset i Trondheim, National Institutes of Health, University of California, Los Angeles, Fakultet for medisin og helsevitenskap, Norges Teknisk-Naturvitenskapelige Universitet, Faculty of Medicine and Health, University of Sydney, National Heart, Lung, and Blood Institute, National Institute of Mental Health, National Institute on Drug Abuse, National Human Genome Research Institute, NIH Office of the Director, National Cancer Institute, National Institute of Neurological Disorders and Stroke, Common Fund
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