The role of cerebrospinal fluid metabolites in the pathogenesis of lung adenocarcinoma: An observational study using Mendelian randomization

The causal relationship between Cerebrospinal fluid (CSF) and lung adenocarcinoma (LUAD) is still uncertain. This study aims to identify the genetically predicted causality of CSF on LUAD through Mendelian randomization (MR). This study utilized a two-sample MR approach to examine the causal relationship between CSF metabolites and LUAD. Data for LUAD was obtained from a large genome-wide association study (GWAS) including 11,273 lung cancer patients and 55,483 controls of European descent. Genetic instrumental variables for CSF metabolites were selected based on SNPs significantly associated with each metabolite. The inverse variance weighting (IVW) method was used for causal effect estimation, and sensitivity analyses (e.g., MR-Egger, weighted median) were conducted to assess pleiotropy and heterogeneity. Both forward and reverse MR analyses were performed to explore bidirectional causality. Forward MR identified 7 CSF metabolites that were causally associated with LUAD risk. Six metabolites, including glycerophosphoinositol and glutamate, were found to increase LUAD risk, while X-24295 was protective. Reverse MR revealed that LUAD affected the levels of specific CSF metabolites, including 1-linoleoyl-gpc and hydroxyasparagine, which were increased, while others like pyroglutamine and 2-hydroxyadipate were decreased. These findings highlight the complex metabolic interactions between LUAD and CSF metabolites. Genetically predicted CSF metabolites play a potentially causal role in the occurrences of LUAD.