Language

English

Publication Date

7-27-2026

Journal

Journal of Thrombosis and Haemostasis

DOI

10.1016/j.jtha.2026.06.046

PMID

42508647

PMCID

PMC13529309

PubMedCentral® Posted Date

9-1-2026

PubMedCentral® Full Text Version

Author MSS

Abstract

Background: Venous thromboembolism (VTE) includes deep vein thrombosis (DVT) and pulmonary embolism (PE), the latter of which often originates from DVT and can be fatal.

Objectives: The aim of this study was to identify causal genetic factors that alter risk of PE among those with a presumed DVT.

Methods: Using a case-only design of VTE, we conducted meta-analyses of genome-wide association studies (GWASs) in the International Network Against Venous Thrombosis Consortium. Among participants diagnosed with VTE, each study identified those who had a clinically reported PE, with or without a clinically reported DVT; those remaining had isolated DVT. Logistic regression models (PE as outcome compared with isolated DVT) were used for variant discovery and replication analyses. A polygenic risk score was created from the GWAS findings. Transcriptome-wide association study analyses were conducted using the GWAS discovery estimates.

Results: Our discovery and replication analyses included 126 316 individuals with a VTE across 29 studies: 54 389 who had a PE and the remaining 71 927 who had an isolated DVT. Five variants reached genome-wide significance (P < 5 × 10-8) in discovery, 4 of which replicated: F5 rs6025 (factor V Leiden), odds ratio (OR) 0.66; FGG rs2066864, OR 1.08; F11 rs4253417, OR 1.07; and SLC12A2-DT rs3749748, OR 0.92. Each 1 SD increase in the polygenic risk score was associated with risk (OR: 1.05; 95% CI: 1.003-1.094). Transcriptome-wide association study analysis identified genetic associations with FGG, SLC12A2-DT, and CDHR4 transcripts.

Conclusion: Although the overall risk for VTE is strongly heritable, our findings support the hypothesis that PE in the setting of a presumed DVT is regulated by genetics, although the overall effect appears modest.

Keywords

Venous Thromboembolism, Pulmonary Embolism, Venous Thrombosis, Genome-Wide Association Study, Transcriptome Analysis, Genetic Risk Score, Molecular Epidemiology

Published Open-Access

yes

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