Abstract Body (Do not enter title and authors here): Background: Abdominal aortic aneurysm (AAA) is a common and life-threatening vascular disease. Genetic studies have identified numerous associated loci, many potentially encoding plasma proteins. However, the causal effects of plasma proteins on AAA have not been thoroughly studied. We used genetic causal inference approaches to identify plasma proteins that have a potential causal impact on AAA.

Methods: Causal inference was performed using two-sample Mendelian randomization (MR). For AAA, we utilized recently published summary statistics from a multi-population genome-wide association (GWAS) meta-analysis including 39,221 individuals with, and 1,086,107 individuals without, AAA from 14 cohorts. We used protein quantitative trait loci (pQTLs) identified in two large-scale plasma-proteomics studies (deCODE and UKB-PPP) to generate genetic instruments. We tested 2409 plasma proteins for possible causal effects on AAA using two-sample MR with inverse variance weighting and common sensitivity analyses to evaluate the MR assumptions. Bayesian colocalization and gene ontology (GO) enrichment analyses provided additional insights.

Results: MR identified 77 plasma proteins whose levels were associated with AAA at FDR<0.05. Of these proteins, 21/77 (27%) were supported by colocalization analysis (posterior probability H4>0.7), indicating that the plasma levels and AAA likely shared causal variants. Among those supported by both MR and colocalization were previously experimentally validated proteins such as PCSK9 (OR 1.3; 95%CI 1.2-1.4; P<1e-10), along with proteins such as LTBP4 (OR 3.4; 95%CI 2.6-4.6; P<1e-10) and COL6A3 (OR 0.6; 95%CI 0.5-0.7; P<1e-6). GO analysis revealed an enrichment of proteins found in extracellular matrix (ECM, OR 7.8; P<1e-4). Gene expression data suggested that some of these ECM proteins have maximal mRNA levels in aortic tissue. Reverse MR for these ECM proteins found no association between genetic liability for AAA and changes in circulating levels of the proteins – suggesting that changes in their plasma levels were not caused by the aneurysm itself.

Conclusions : Our results highlight proteins and pathways with potential causal effects on AAA, providing a foundation for future functional experiments. These findings suggest a possible causal pathway whereby genetic variation affecting ECM proteins expressed in the aortic wall cause their levels to change in blood plasma while simultaneously facilitating the formation of AAA.