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

1 PGESG - BOSTON - Program in Genetic Epidemiology and Statistical Genetics
2 University of Washington [Seattle]
3 The Scripps Translational Science Institute and Scripps Health
4 Department of Thrombosis and Haemostasis
5 HSR - Department of Health Sciences Research [Mayo Clinic]
6 University of Minnesota System
7 FHCRC - Fred Hutchinson Cancer Research Center [Seattle]
8 Brigham and Women's Hospital [Boston]
9 C2VN - Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research
10 Laboratoire d'hématologie biologique [Hôpital de la Timone - Hôpital Nord - APHM]
11 NIH - National Institutes of Health [Bethesda]
12 Harvard T.H. Chan School of Public Health
13 ICAN - Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases
14 University of Washington - Biorobotics Lab
15 USN - University of South-Eastern Norway
16 Department of Health Sciences Research
17 OSU - Ohio State University [Columbus]
18 NORT - Nutrition, obésité et risque thrombotique
19 LA BioMed - Los Angeles Biomedical Research Institute
20 UNIA - University of Augsburg
21 CNG - Centre National de Génotypage
22 Department of Epidemiology
23 Leiden University Medical Center (LUMC)
24 Division of Cardiovascular Diseases
25 UMN - University of Minnesota [Twin Cities]
26 NTNU - Norwegian University of Science and Technology [Trondheim]
27 Department of Emergency Medicine

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.

Domains: Life Sciences [q-bio]

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⟩