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

Sara Lindström, 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 PankratzRebecca 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 François 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 Trégouët, Nicholas L. Smith

Research output: Contribution to journalArticle

11 Scopus citations

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 transcriptomewide 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.

Original languageEnglish (US)
Pages (from-to)1645-1657
Number of pages13
JournalBlood
Volume134
Issue number19
DOIs
StatePublished - Nov 7 2019

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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    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., ... Smith, N. L. (2019). Genomic and transcriptomic association studies identify 16 novel susceptibility loci for venous thromboembolism. Blood, 134(19), 1645-1657. https://doi.org/10.1182/blood.2019000435