Plasma Circulating Proteins and Intracranial Aneurysm Susceptibility: A Proteome-Wide Mendelian Randomization Analysis.

Abstract

Intracranial aneurysms (IAs) are cerebrovascular diseases with exceptionally high mortality and disability rates. Preventing and treating IA are crucial steps toward reducing the burden of these conditions. We propose conducting a proteome Mendelian randomization study to investigate key plasma proteins that influence IA and to identify biomarkers and therapeutic targets for their prevention and treatment. We used 2100 plasma proteins from 9 studies as exposures and IA GWAS data from the UK Biobank as outcomes to explore the major plasma proteins influencing IA. The primary method of this study was inverse variance weighting or Wald ratio. To test the robustness of the findings, sensitivity analyses were performed using various approaches, including PheWAS, reverse Mendelian randomization, and others. Finally, GWAS data on IA from 473,683 European patients were used as replication data. Protein-protein interaction networks, Drugbank/DGIdb, and other methods were employed to discover potential therapeutic targets. After False Discovery Rate correction, we identified that biotinidase (BTD) (odds ratio [OR = 0.6489, 95% confidence interval [CI]: 0.5520-0.7628, P = 1.59 × 10^-7) and Fc alpha receptor (OR = 0.6798, 95% CI: 0.5620-0.8223, P = 7.03 × 10^-5) reduced the risk of IA, while versican (VCAN) (OR = 1.4190, 95% CI: 1.1976-1.6815, P = 5.29 × 10^-5) increased the risk of IA according to the inverse variance weighting method. Sensitivity analyses confirmed that the robustness of the results was not affected by heterogeneity, pleiotropy, or reverse causality. During the replication phase, BTD (OR = 0.9141, 95% CI: 0.8383-0.9967, P = 0.04) was found to potentially decrease IA risk; however, the association among VCAN (OR = 0.9602, 95% CI: 0.9136-1.0092, P = 0.11), Fc alpha receptor (OR = 1.0031, 95% CI: 0.9576-1.0507, P = 0.90), and the risk of IA was not verified. Additionally, protein-protein interaction and other methods suggest that VCAN may be a potential drug target for IA. Circulating protein BTD reduces the risk of IA and may serve as a key biomarker and preventive target for IA.