Liu Shuming, Guan Huiyuan, Wang Feng
Department of Interventional Therapy, the First Affiliated Hospital of Dalian Medical University, Dalian, China.
Department of Breast Surgery,the Huzhou Maternal and Child Health Hospital, Huzhou, China.
Clin Neurol Neurosurg. 2025 Feb;249:108749. doi: 10.1016/j.clineuro.2025.108749. Epub 2025 Jan 21.
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.
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.
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.
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.
目前，尽管一些研究对未破裂颅内动脉瘤（uIAs）相关的遗传因素提供了一定见解，但与uIAs相关的潜在遗传靶点仍在很大程度上未知。因此，本研究采用孟德尔随机化（MR）分析来研究两项关于uIAs的全基因组关联研究，旨在确定uIAs可靠的遗传易感性和潜在治疗靶点。
本研究总结表达数量性状基因座（eQTL）的数据作为暴露数据。uIAs的结局数据来自Bakker等人的研究以及芬兰生物银行（版本R10）。通过孟德尔随机化（MR）方法确定uIAs可靠的遗传易感性和潜在治疗靶点，以逆方差加权（IVW）方法作为主要分析方法。同时，进行敏感性和多效性分析，并将结果可视化。随后，对潜在基因靶点进行药物预测和分子对接以验证其可靠性。
训练队列的MR分析确定了100个与uIAs相关的靶点。然后，使用测试队列通过MR分析再次验证这100个基因靶点和eQTL数据。最后，选择了7个基因靶点，即MTMR3、SERINC1、CITED2、NKX3-1、ATOX1、MYADM和SLC20A1-DT。基因本体论/京都基因与基因组百科全书（GO/KEGG）富集分析证实，这7个基因靶点主要参与动脉发育、细胞对缺氧的反应、雄性性腺发育、RNA聚合酶II特异性DNA结合转录因子结合、DNA结合转录因子结合、矿物质吸收、肌醇磷酸代谢、磷脂酰肌醇信号系统等生物学功能和途径。蛋白质-蛋白质相互作用（PPI）网络描述了7个基因靶点与相关蛋白质之间的相互作用。分子对接图显示候选药物与基因靶点相关蛋白质之间具有良好的结合。
该研究确定了7个与uIAs相关的可靠基因易感性和潜在治疗靶点，为uIAs的临床诊断和治疗提供了新见解，并为理解uIAs的病因和分子机制提出了新的研究方向。
