TY - JOUR
T1 - Genomic and transcriptomic association studies identify 16 novel susceptibility loci for venous thromboembolism
AU - Lindström, Sara
AU - Wang, Lu
AU - Smith, Erin N.
AU - Gordon, William
AU - Van Hylckama Vlieg, Astrid
AU - De Andrade, Mariza
AU - Brody, Jennifer A.
AU - Pattee, Jack W.
AU - Haessler, Jeffrey
AU - Brumpton, Ben M.
AU - Chasman, Daniel I.
AU - Suchon, Pierre
AU - Chen, Ming Huei
AU - Turman, Constance
AU - Germain, Marine
AU - Wiggins, Kerri L.
AU - MacDonald, James
AU - Braekkan, Sigrid K.
AU - Armasu, Sebastian M.
AU - Pankratz, Nathan
AU - Jackson, Rebecca D.
AU - Nielsen, Jonas B.
AU - Giulianini, Franco
AU - Puurunen, Marja K.
AU - Ibrahim, Manal
AU - Heckbert, Susan R.
AU - Damrauer, Scott M.
AU - Natarajan, Pradeep
AU - Klarin, Derek
AU - De Vries, Paul S.
AU - Sabater-Lleal, Maria
AU - Huffman, Jennifer E.
AU - Bammler, Theo K.
AU - Frazer, Kelly A.
AU - McCauley, Bryan M.
AU - Taylor, Kent
AU - Pankow, James S.
AU - Reiner, Alexander P.
AU - Gabrielsen, Maiken E.
AU - Deleuze, Jean François
AU - O'Donnell, Chris J.
AU - Kim, Jihye
AU - McKnight, Barbara
AU - Kraft, Peter
AU - Hansen, John Bjarne
AU - Rosendaal, Frits R.
AU - Heit, John A.
AU - Psaty, Bruce M.
AU - Tang, Weihong
AU - Kooperberg, Charles
AU - Hveem, Kristian
AU - Ridker, Paul M.
AU - Morange, Pierre Emmanuel
AU - Johnson, Andrew D.
AU - Kabrhel, Christopher
AU - Trégouët, David Alexandre
AU - Smith, Nicholas L.
N1 - Funding Information:
Conflict-of-interest disclosures: B.M.P. serves on the Steering Committee of the Yale Open Data Access project funded by Johnson & Johnson.
Funding Information:
P.N. has received grant support from Amgen, Apple, and Boston Scientific and is a scientific advisor to Apple. S.M.D. receives institutional funding from CytoVas LLC and RenalytixAI. The remaining authors declare no competing financial interests.
Funding Information:
This work was supported in part by National Institutes of Health, National Heart, Lung, and Blood Institute grants HL134894, HL139553, and HL141791 (N.L.S.). The K.G. Jebsen Thombosis Research and Expertise Center is supported by an independent grant from Stiftelsen Kristian Gerhard Jebsen (J.H.) and HL116854 (C. Kabrhel). Sources of funding for the specific cohorts can be found in the supplemental Materials.
Publisher Copyright:
© 2019 American Society of Hematology. All rights reserved.
PY - 2019/11/7
Y1 - 2019/11/7
N2 - 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.
AB - 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.
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U2 - 10.1182/blood.2019000435
DO - 10.1182/blood.2019000435
M3 - Article
C2 - 31420334
AN - SCOPUS:85074331473
VL - 134
SP - 1645
EP - 1657
JO - Blood
JF - Blood
SN - 0006-4971
IS - 19
ER -