Abstract Number: OC 56.1
Meeting: ISTH 2022 Congress
Background: Venous thromboembolism (VTE) is a cardiovascular event that manifests as deep vein thrombosis or pulmonary embolism. Over the last decade, genetic association studies uncovered up to 40 genetic loci associated with VTE risk.
Aims: To discover novel gene loci influencing VTE risk and extend our understanding of the genetic architecture of VTE, we conducted an expanded meta-analysis of VTE genome wide association studies (GWAS).
Methods: We meta-analyzed GWAS results from 14 studies, which included 81,669 VTE cases and over a million controls from European, African, Hispanic, East and South-Asian ancestries. We first conducted a cross-ancestry discovery meta-analysis using a subset of 4 studies (Nf55,330 cases), while the remaining studies were reserved to replicate discovery loci that exceeded the significance threshold (P < 5x10-8). The discovery and replication studies were then meta-analyzed to create a combined, cross-ancestry dataset along with Europeans and Africans ancestry-specific meta-analyses. Subsequent analyses included fine-mapping, transcriptome and proteome-wide association analyses.
Results: The discovery meta-analysis revealed 85 genome-wide significant loci, including 48 mapping to gene loci that were not previously reported for VTE. In the replication study, 46 out of the 48 novel loci had a concordant effect direction with the discovery analysis, of which 34 passed the Bonferroni-corrected significance threshold, including 3 involving variants with low frequency and large effect sizes: ST3GAL4 (frequency=0.021, OR=1.19), ZMIZ1 (frequency=0.029, OR=1.12) and MAP1A (frequency=0.027, OR=0.85). The combined and ancestry-stratified meta-analyses established an additional 46 novel signals reaching genome-wide significance. Conditional analyses revealed secondary signals at 20 loci, while proteome and transcriptome analyses identified putative genes at novel loci (e.g. TIMP3, TIMP4 and NFE2). VTE variants discovered with these analyses were mostly associated with blood traits, and platelet traits in particular.
Conclusion(s): This work substantially increases the known VTE genetic loci, unveiling new insights on the etiology of the disease and potential opportunities for new targeted treatments.
To cite this abstract in AMA style:Thibord F, Klarin D, Chasman D, Teder-Laving M, Goode E, Hveem K, Martinez-Perez A, Emmerich J, Jouven X, Ito K, Cuellar Partida G, Haessler J, Hansen J, van Hylckama Vlieg A, Morange P, Kabrhel C, Tregouet D, Damrauer S, Johnson A, Smith N. A Cross-Ancestry Meta-Analysis of Venous Thromboembolism Genetic Associations [abstract]. https://abstracts.isth.org/abstract/a-cross-ancestry-meta-analysis-of-venous-thromboembolism-genetic-associations/. Accessed August 8, 2022.
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