Integrative bioinformatics frameworks for abdominal aortic aneurysm using GWAS meta-analysis, biological network construction, and structural modeling.

Abdominal aortic aneurysm (AAA) is a non-communicable disease (NCD) with high morbidity and mortality, commonly observed worldwide. Understanding its molecular mechanisms and identifying potential therapeutic targets are crucial for disease screening, diagnosis, and treatment. In this study, we conducted a meta-analysis of multiple genome-wide association studies (GWASs) to identify genetic variants associated with AAA and explored the functional implications of these variants in disease pathology. We identified differentially expressed genes (DEGs) based on significant single nucleotide polymorphisms (SNPs) from expression quantitative trait loci (eQTL) and transcriptome-wide association study (TWAS) analyses. Using these DEGs, we constructed an AAA-related protein-protein interaction (PPI) network and prioritized key genes for further analysis. Furthermore, we performed drug repurposing by identifying drug-gene and drug-protein interactions in existing databases and validated potential candidates through molecular docking. Our findings reveal 42 novel disease-associated SNPs and 52 previously unreported disease-related genes. Some residual confounding factors cannot be fully ruled out and may represent a limitation of our study. However, it is worth noting that only a minority of SNPs exhibited heterogeneity. Functional pathways analysis highlighted key processes, including lipid and cholesterol metabolism, tissue remodeling, and acetylcholine activation. We identified 74 DEGs through eQTL and TWAS analyses, with PPI network analysis highlighting CD40 and LRP1 as key proteins. Drug repurposing and molecular docking suggested abciximab and paclitaxel as potential therapeutic agents targeting CD40, while ivermectin emerged as a strong candidate for LRP1 binding. In conclusion, our integrative bioinformatics frameworks links genomics and transcriptomics with network biology and structural modeling, providing valuable insights into the molecular mechanisms of AAA and potential therapeutic strategies.