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

TitleGenomic and transcriptomic association studies identify 16 novel susceptibility loci for venous thromboembolism.
Publication TypeJournal Article
Year of Publication2019
AuthorsLindström S, Wang L, Smith EN, Gordon W, Vlieg Avan Hylcka, de Andrade M, Brody JA, Pattee JW, Haessler J, Brumpton BM, Chasman DI, Suchon P, Chen M-H, Turman C, Germain M, Wiggins KL, MacDonald J, Braekkan SK, Armasu SM, Pankratz N, Jackson RD, Nielsen JB, Giulianini F, Puurunen MK, Ibrahim M, Heckbert SR, Damrauer SM, Natarajan P, Klarin D, de Vries PS, Sabater-Lleal M, Huffman JE, Bammler TK, Frazer KA, McCauley BM, Taylor K, Pankow JS, Reiner AP, Gabrielsen ME, Deleuze J-F, O'Donnell CJ, Kim J, McKnight B, Kraft P, Hansen J-B, Rosendaal FR, Heit JA, Psaty BM, Tang W, Kooperberg C, Hveem K, Ridker PM, Morange P-E, Johnson AD, Kabrhel C, Tregouet D-A
Secondary AuthorsSmith NL
Corporate AuthorsMillion Veteran Program, CHARGE Hemostasis Working Group
JournalBlood
Volume134
Issue19
Pagination1645-1657
Date Published2019 11 07
ISSN1528-0020
KeywordsGenetic Predisposition to Disease, Genome-Wide Association Study, Humans, Venous Thromboembolism
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.

DOI10.1182/blood.2019000435
Alternate JournalBlood
PubMed ID31420334
PubMed Central IDPMC6871304
Grant ListR01 HL139553 / HL / NHLBI NIH HHS / United States
R61 HL141791 / HL / NHLBI NIH HHS / United States
R01 HL116854 / HL / NHLBI NIH HHS / United States
R33 HL141791 / HL / NHLBI NIH HHS / United States
U01 CA182913 / CA / NCI NIH HHS / United States
R01 HL134894 / HL / NHLBI NIH HHS / United States