Exploring the role of 338 cerebrospinal fluid metabolites in primary brain malignancies risk: a Mendelian...

Cerebrospinal fluid (CSF) metabolites are implicated in various neurological disorders, but their relationship with primary brain malignancies remains unclear. This study aims to use a two-sample Mendelian randomization (MR) approach to evaluate the role of CSF metabolites in the development of primary brain malignancies.

Data on 338 human CSF metabolites were obtained from a genome-wide association study (GWAS) involving 291 participants. The information on primary brain malignancies was derived from a large-scale GWAS summary, which included 816 cases and 314,193 controls of European ancestry. The inverse-variance weighted model was used as the primary analysis method, supplemented by sensitivity analyses such as heterogeneity testing, horizontal pleiotropy testing, and leave-one-out analysis. Linkage disequilibrium score regression was performed for genetic correlation analysis.

This study identified ten CSF metabolites whose associations with primary brain malignancies are consistent with a potential causal role (0.0001 < P < 0.05), including one unidentified metabolite. Of these, five metabolites were positively correlated with the risk of disease, while four showed a negative correlation. Notably, after FDR correction, the causal association between elevated levels of 5-methylthioadenosine (MTA) and increased risk of primary brain malignancies remained (P = 0.038), and there was no evidence of reverse causality between the two, suggesting that MTA may be an important risk factor for primary brain malignancies.

The findings provide evidence consistent with potential causal associations between ten CSF metabolites and primary brain malignancies, helping us to further understand the pathogenesis of primary brain malignancies and provide clues for the prediction of the disease.