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

Sara Lindström 1 Lu Wang 2 Erin N. Smith 3 William Gordon 1 Astrid van Hylckama Vlieg 4 Mariza de Andrade 5 Jennifer Brody 2 Jack Pattee 6 Jeffrey Haessler 7 Ben Brumpton Daniel Chasman 8 Pierre Suchon 9, 10 Ming-Huei Chen 11 Constance Turman 12 Marine Germain 13 Kerri Wiggins 14 James Macdonald 14 Sigrid Braekkan 15 Sebastian Armasu 16 Nathan Pankratz Rebecca D. Jackson 17 Jonas Nielsen Franco Giulianini Marja Puurunen Manal Ibrahim 18 Susan Heckbert Scott Damrauer Pradeep Natarajan Derek Klarin Paul de Vries Maria Sabater-Lleal Jennifer Huffman Theo Bammler Kelly Frazer Bryan Mccauley Kent D Taylor 19 James Pankow Alexander Reiner 20 Maiken Gabrielsen Jean-François Deleuze 21 Chris O'Donnell Jihye Kim Barbara Mcknight Peter Kraft 22 John-Bjarne Hansen Frits Rosendaal 23 John Heit 24 Bruce Psaty 2 Weihong Tang 25 Charles Kooperberg Kristian Hveem 26 Paul Ridker 8 Pierre-Emmanuel Morange 9, 10 Andrew Johnson Christopher Kabrhel 27 David-Alexandre Trégouët 13 Nicholas Smith 
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 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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Submitted on : Tuesday, April 14, 2020 - 5:04:33 PM
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Sara Lindström, Lu Wang, Erin N. Smith, William Gordon, Astrid van Hylckama Vlieg, et al.. Genomic and transcriptomic association studies identify 16 novel susceptibility loci for venous thromboembolism. Blood, 2019, 134 (19), pp.1645-1657. ⟨10.1182/blood.2019000435⟩. ⟨hal-02542549⟩



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