Genome-wide association study-driven identification of thrombomodulin and factor V as the best biomarker combination for deep vein thrombosis

Figures

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  Fig. 1. Workflow of the study for identifying blood-based biomarkers of DVT. 1 Data Extraction: SNPs associated with DVT were extracted from the EBI-NHGRI GWAS Catalog, with a Manhattan plot used to visualize the significant SNPs. A total of 689 SNPs were identified, with 458 SNPs passing the threshold of p < 5.10−⁸. 2 Computational analysis: using HaploReg, SNP variants were analyzed, identifying 4430 SNP variants linked to 334 genes. 3 Functional Annotations: Genes were prioritized based on seven biological risk criteria to identify those with a strong association with DVT, resulting in 28 risk genes. 4 Enrichment and Tissue Expression: GO (Gene Ontology) analysis, network analysis, and tissue-specific gene expression highlighting THBD and F5 as the most promising blood-based biomarkers for DVT

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  Fig. 2. Manhattan plot of SNPs associated with DVT. 689 SNPs across chromosomes are shown with -log10 (p-value) on the y-axis, highlighting significant associations with DVT. Peaks on chromosomes 1, 4, 9, and 13 indicate SNPs loci that may influence DVT susceptibility. The black dashed line represents the genome-wide significance threshold (p = 5 × 10⁻⁸). The red dashed line indicates an additional threshold corresponding to the top 40 SNPs, based on visual prominence

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  Fig. 3. Gene ontology (GO) enrichment analysis of biological processes related to DVT-associated genes. This bar plot illustrates the enriched biological processes for genes associated with DVT, indicated by enrichment ratio and adjusted by false discovery rate (FDR). Notably, 15 genes involved in coagulation, regulation of response to wounding, and wound healing (FDR ≤ 0.05). These processes highlight the involvement of these genes in clot formation and tissue repair mechanisms, providing valuable insights into their roles in DVT pathogenesis

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  Fig. 4. Network analysis of key genes associated with DVT and thrombophilia. This network illustrates the relationships between genes (green nodes), human phenotypes (blue nodes), and disease ontologies linked to DVT and thrombophilia. The highlighted genes F5, F2, F9, PROC, and THBD show direct connections (red lines) to DVT, underscoring their central role in coagulation pathways and thrombotic risk. This network highlights gene-phenotype and gene-disease associations that may contribute to the genetic susceptibility and pathogenesis of thrombotic disorders

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  Fig. 5. Gene expression profiles of DVT-associated genes in liver and whole blood. Violin plots representing the bulk tissue gene expression of five key genes associated with DVT: F9, F2, PROC, F5, and THBD. Each plot shows expression levels in liver (green) and whole blood (pink) tissues, as analyzed from GTEx data. THBD and F5 exhibit significant expression in whole blood, suggesting their potential as blood-based biomarkers for DVT. In contrast, F2, F9, and PROC show higher expression levels in the liver, indicating a more organ-specific role. The broad expression of THBD and F5 in whole blood highlights their suitability biomarker of DVT