脑脊液代谢物与胶质母细胞瘤因果关系研究——一项两样本孟德尔随机化分析研究

Causal Relationship Analysis between Cerebrospinal Fluid Metabolites and Glioblastoma—A Two-Sample Mendelian Randomization Study

摘要: 胶质母细胞瘤是致死率极高的原发性脑肿瘤，中位生存期不足15个月。随着基因组学技术及算力迭代升级，如全基因组关联分析、代谢组学等研究方法已较为成熟，推动了以单核苷酸多态性作为工具变量探索因果关系的孟德尔随机化分析的进展。本研究基于双向两样本孟德尔随机化方法，分别利用FinnGen与IEU Open GWAS数据库中有关胶质母细胞瘤及脑脊液代谢物的数据，分析两者间的因果效应。主分析采用逆方差加权法，辅以MR-Egger、加权中位数等敏感性分析。结果显示15种脑脊液代谢物与胶质母细胞瘤相关，其中8种呈显著负相关、7种呈正相关，且反向孟德尔随机化无阳性发现，提示这些关联具有方向特异性，支持脑脊液代谢物水平可能作为胶质母细胞瘤的潜在因果风险或保护因素，而非疾病后果。

Abstract: Glioblastoma (GBM) is a highly lethal primary brain tumor with a median survival of under 15 months. Advances in genomic technologies and computational power have accelerated genome-wide association studies (GWAS) and metabolomics, enabling Mendelian randomization (MR)—a method that uses single nucleotide polymorphisms (SNPs) as instrumental variables to infer causal relationships. In this study, we applied bidirectional two-sample MR to evaluate the causal relationship of cerebrospinal fluid (CSF) metabolites with GBM, using GWAS summary statistics sourced from the FinnGen consortium and the IEU Open GWAS database. Primary analysis used the inverse-variance weighted (IVW) method, supplemented by sensitivity analyses including MR-Egger and weighted median approaches. The results identified 15 CSF metabolites significantly associated with GBM risk—eight inversely and seven positively. Notably, reverse MR analyses yielded no significant associations, supporting a unidirectional causal effect and suggesting that altered CSF metabolite levels may serve as upstream risk or protective factors in GBM pathogenesis, rather than being secondary consequences of the disease.