Genetic susceptibility and potential therapeutic targets of unruptured intracranial aneurysms: A genome-wide study based on Mendelian randomization

Background: At present, although some studies have offered certain insights into the genetic factors related to unruptured intracranial aneurysms (uIAs), the potential genetic targets associated with uIAs remain largely unknown. Thus, this research adopted Mendelian randomization (MR) analysis to study two genome-wide association studies on uIAs, aiming to determine the reliable genetic susceptibility and potential therapeutic targets for uIAs. Methods: This study summarizes the data of expression quantitative trait loci (eQTL) as exposure data. The outcome data of uIAs were derived from the study by Bakker et al. and the FinnGen Biobank (version R10). The reliable genetic susceptibility and potential therapeutic targets of uIAs were identified by means of Mendelian randomization (MR) methods, with the inverse variance weighting (IVW) method as the primary analytical approach. Simultaneously, sensitivity and pleiotropy analyses were carried out, and the results were visualized. Subsequently, drug predictions and molecular docking were conducted for the potential gene targets to verify their reliability. Results: The MR analysis of the training cohort identified 100 targets related to uIAs. Then, these 100 gene targets and eQTL data were verified by MR Analysis again with the testing cohort. Finally, 7 gene targets were selected, namely MTMR3, SERINC1, CITED2, NKX3-1, ATOX1, MYADM and SLC20A1-DT.GO/KEGG enrichment analysis confirmed that the 7 gene targets mainly participate in the process Biological functions and pathways such as art development, cellular response to hypoxia, male Gonad development, RNA polymerase II specific DNA binding transcription factor binding, DNA binding transcription factor binding, Mineral absorption, Inositol phase metabolism, Photoshatidylinositol signaling system, etc.The protein-protein interaction(PPI) network describes the interactions between seven gene targets and related proteins.The molecular docking diagram shows good binding between candidate drugs and proteins related to gene targets. Conclusions: The study identified 7 reliable gene susceptibility and potential therapeutic targets associated with uIAs, offering new insights for clinical diagnosis and treatment of uIAs, and suggesting novel research directions for understanding the etiology and molecular mechanisms of uIAs.