Evaluating the Causal Effects of Serum and Cerebrospinal Fluid Metabolites on Cerebral Palsy: A Whole-Metabolome Mendelian Randomization Study

Abstract

Purpose

This study aimed to investigate the causal relationships between serum and cerebrospinal fluid (CSF) metabolites and cerebral palsy (CP) risk, leveraging genetic insights to identify potential biomarkers and metabolic pathways implicated in CP pathogenesis.

Method

A two-sample Mendelian randomization (MR) approach was employed to analyze 1400 serum metabolites and 338 CSF metabolites. Genetic variants associated with metabolite levels were used as instrumental variables (IVs) to infer causal effects on CP risk.

Findings Serum Metabolites

Sixty-nine metabolites showed significant associations with CP risk, including 1-(1-enyl-stearoyl)-2-linoleoyl-GPE (protective effect: odd ratio [OR] = 0.84, p = 0.001) and 1,2-dipalmitoyl-GPC (risk effect: OR = 1.12, p = 0.003). CSF metabolites: 13 metabolites were significantly linked to CP, most notably 1-palmitoyl-2-palmitoleoyl-GPC (OR = 0.57, p = 0.001). Shared biomarker: Methionine sulfone exhibited protective effects in both serum and CSF. Pathway analysis: Glyoxylate/dicarboxylate metabolism and butyrate metabolism emerged as key pathways potentially influencing CP pathogenesis.

Conclusion

This MR study provides novel evidence supporting the causal role of serum and CSF metabolites in CP, highlighting methionine sulfone and specific metabolic pathways as biologically significant factors. Although limitations such as sample size constraints and lack of experimental validation warrant caution, these findings underscore the therapeutic potential of targeting metabolic pathways in CP. Future research should prioritize mechanistic studies and translational exploration of identified metabolites.