探索基因预测的血液和脑脊液代谢物和代谢途径对颅内动脉瘤的因果关系

摘要(中文译文)

目的既往研究已发现颅内动脉瘤患者体内代谢物存在显著改变。本研究旨在利用双向孟德尔随机化分析，在遗传层面评估血液和脑脊液中代谢物与颅内动脉瘤之间的因果关系。方法从一项纳入8299名个体的全基因组关联研究分析中获取1400种血液代谢物的遗传工具变量，同时从另一项纳入291名个体的全基因组关联研究中获取338种脑脊液代谢物。颅内动脉瘤的结局数据取自国际卒中遗传学联盟，验证数据取自FinnGen研究。主要分析采用逆方差加权法，并辅以敏感性分析以处理多效性并增强稳健性。通过重复分析和荟萃分析增强研究结果的稳健性。采用共定位分析评估代谢物与颅内动脉瘤之间可能存在的共享遗传结构，并使用MetaboAnalyst 6.0进行代谢通路分析。结果经错误发现率校正后，在发现组中分别有4种和5种遗传预测的血液代谢物与颅内动脉瘤和蛛网膜下腔出血呈反向因果关联，而脑脊液代谢物与三种颅内动脉瘤表型均未显示显著因果关联。在纳入重复数据结果进行荟萃分析后，我们确定1-花生四烯酰-GPC（20:4n6）（比值比：0.90）和1-棕榈酰-2-花生四烯酰-GPC（16:0/20:4n6）（比值比：0.92）为颅内动脉瘤的潜在保护因素，以及（N(1) + N(8)）-乙酰精胺（比值比：0.83）为蛛网膜下腔出血的潜在保护因素。结论我们的研究结果确立了血液/脑脊液代谢物与颅内动脉瘤之间潜在的因果联系。此外，所鉴定的代谢物和通路为颅内动脉瘤的致病机制和进展提供了有价值的见解。

Abstract

ObjectivePrevious studies have identified significant alterations in metabolites in patients with intracranial aneurysm. This study aimed to evaluate the causal relationships of metabolites in both blood and cerebrospinal fluid with intracranial aneurysm at the genetic level using bidirectional Mendelian randomization analysis.MethodsGenetic instrumental variables for 1400 blood metabolites were obtained from a genome-wide association study analysis involving 8299 individuals, while 338 cerebrospinal fluid metabolites were sourced from another genome-wide association study involving 291 individuals. Outcome data for intracranial aneurysm were retrieved from the International Stroke Genetics Consortium, and validation data were retrieved from the FinnGen study. The primary analysis employed the inverse-variance weighted method, supported by sensitivity analysis to address pleiotropy and enhance robustness. Replication analysis and meta-analysis were performed to enhance the robustness of the findings. Colocalization analysis was used to assess the potential shared genetic architecture between metabolites and intracranial aneurysm, and metabolic pathway analysis was performed using MetaboAnalyst 6.0.ResultsFollowing false discovery rate correction, four and five genetically predicted blood metabolites showed inversely causal associations with intracranial aneurysms and subarachnoid hemorrhage, respectively, in the discovery group, while no cerebrospinal fluid metabolites showed significant causal associations with three intracranial aneurysm phenotypes. After performing a meta-analysis incorporating the results from the replication data, we identified 1-arachidonoyl-GPC (20:4n6) (odds ratio: 0.90) and 1-palmitoyl-2-arachidonoyl-GPC (16:0/20:4n6) (odds ratio: 0.92) as potential protective factors against intracranial aneurysms as well as (N(1) + N(8))-acetylspermidine (odds ratio: 0.83) as a potential protective factor against subarachnoid hemorrhage.ConclusionsOur findings establish a potential causal link between blood/cerebrospinal fluid metabolites and intracranial aneurysm. Furthermore, the identified metabolites and pathways provide valuable insights into the pathogenic mechanisms and progression of intracranial aneurysm.

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