Plasma proteome-wide Mendelian Randomization reveals the association of extracellular matrix proteins with abdominal aortic aneurysm

Background
Abdominal aortic aneurysm (AAA) is a common and life-threatening vascular disease. Genetic studies have identified numerous risk 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 2,783 plasma proteins for possible causal effects on AAA using two-sample MR with inverse variance weighting with common sensitivity analyses.
Results
MR identified 90 plasma proteins associated with AAA at FDR<0.05, with 25 supported by colocalization analysis. Among those supported by both MR and colocalization were proteins such as PCSK9 (OR 1.3; 95% CI 1.2-1.4; P<1e-10), 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 enrichment of proteins (ECM, OR 7.8; P<1e-4), some with maximal mRNA levels in aortic tissue. Bi-directional MR suggested plasma level changes were not caused by liability to AAA itself. Colocalization analysis showed that an aortic expression quantitative trait locus (eQTL) for COL6A3, and a splicing quantitative trait locus (sQTL) for LTBP4 colocalized with their respective plasma pQTLs and AAA signals.ConclusionsOur 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, influencing development of AAA.