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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, 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-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 and Nicholas L. Smith

Key Points

  • We identified new genetic loci contributing to the risk of venous thromboembolism, some of which are outside known coagulation pathways.

  • We provide evidence that blood traits may contribute to the underlying biology of venous thromboembolism risk.

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.

  • Submitted March 3, 2019.
  • Revision received August 16, 2019.
  • Accepted July 17, 2019.