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.

**研究目标：** 采用遗传与基因组学方法，鉴定并验证可用于腹主动脉瘤（abdominal aortic aneurysm, AAA）、主动脉瘤（aortic aneurysm, AA）及胸主动脉瘤（thoracic aortic aneurysm, TAA）治疗的潜在靶点基因。
**研究方法：** 本研究采用整合分析策略，涵盖孟德尔随机化（Mendelian randomization, MR）、基于汇总数据的孟德尔随机化（summary-data-based MR, SMR）、贝叶斯共定位分析（eQTLGen、UKB-PPP）及HEIDI检验。首先将可靶向药物基因与顺式表达数量性状位点/蛋白数量性状位点（cis-eQTLs/pQTL）数据进行交集分析以筛选靶点，随后利用芬根研究（FinnGen）与英国生物银行（UK Biobank）队列开展孟德尔随机化分析。通过反向因果检验、异质性检验及多效性检验确保分析结果的稳健性，同时还开展了多变量孟德尔随机化、连锁不平衡得分回归（LDSC）、表型全基因组关联分析（PheWAS）及药物预测分析。
**研究结果：** 孟德尔随机化及验证分析筛选出VIPR1、AGRP、LPL与PROCR这4个与主动脉瘤患病风险显著相关的关键基因。上述基因在发现队列与验证队列中均表现出一致的关联效应，且未检测到显著异质性与水平多效性。SMR与HEIDI检验验证了它们的因果关联，共定位分析进一步支持这一结论。PheWAS与药物预测分析进一步凸显了这些基因作为治疗靶点的潜力，同时也为其在动脉瘤发病机制中的特异性作用提供了证据。
**研究结论：** 本研究阐明了主动脉瘤的遗传结构，鉴定出新型药物靶点，可为此类疾病的精准医学研究提供助力。