Genetic Dissection of Aortic Aneurysms: Identifying Causal Variants and Novel Druggable Targets Through Mendelian Randomization and Multi-Omics Approaches

<strong>Objective:</strong> To identify and validate potential therapeutic genes for abdominal aortic aneurysm (AAA), aortic aneurysm (AA), and thoracic aortic aneurysm (TAA) using genetic and genomic approaches.<strong>Methods:</strong> An integrative strategy was applied, including Mendelian randomization (MR), summary-data-based MR (SMR), Bayesian co-localization (eQTLGen, UKB-PPP), and HEIDI tests. Druggable genes were intersected with cis-eQTLs/pQTL data to identify targets, followed by MR analysis using FinnGen and UK Biobank cohorts. Robustness was ensured via reverse causality, heterogeneity, and pleiotropy tests. Multivariate MR, LDSC, PheWAS, and drug prediction analyses were also performed. <strong>Results:</strong> MR and validation analyses identified VIPR1, AGRP, LPL, and PROCR as key genes significantly associated with aortic aneurysm risk. These genes showed consistent associations across discovery and replication cohorts, with no significant heterogeneity or horizontal pleiotropy. SMR and HEIDI tests confirmed their causal links, supported by colocalization analysis. PheWAS and drug prediction further highlighted their potential as therapeutic targets, with evidence of specific roles in aneurysm pathogenesis.<strong>Conclusions:</strong> This study elucidates the genetic architecture of aortic aneurysms and identifies novel drug targets, facilitating precision medicine for these conditions.