Exploratory bidirectional Mendelian randomisation analysis of cerebrospinal fluid metabolites associated with cerebral palsy and epilepsy.

Authors

Longkun Mao, Ting Cui, Yun Liu, Xianrui Chen, Kaishou Xu

Published in

BMJ paediatrics open. Volume 10. Issue 1. Sep 21, 2026. Epub Sep 21, 2026.

Abstract

Cerebral palsy (CP) and epilepsy are prevalent neurodevelopmental disorders with shared aetiological complexities. This study employs bidirectional Mendelian randomisation (MR) to investigate associations consistent with potential causal effects between cerebrospinal fluid (CSF) metabolites and the pathogenesis of CP and epilepsy.
We conducted a two-sample MR analysis using genome-wide association study (GWAS) data from FinnGen, including 482 CP cases, 11 740 epilepsy cases and European ancestry controls. Instrumental variables for 338 CSF metabolites were selected using a relaxed threshold (p<1×10^-5) due to the modest size of the metabolite GWAS. Nominal statistical significance was defined as p<0.05; to account for multiple comparisons, Benjamini-Hochberg false discovery rate (FDR) correction (Q<0.05) was applied across all five MR methods for each outcome.
Six CSF metabolites showed nominal significant associations with CP risk in inverse variance weighted analyses, after FDR correction, three remained significant: 3-hydroxypyridine sulfate (OR=1.23, Q=0.040), isoleucine (OR=0.49, Q=0.046) and sphingomyelin (OR=1.12, Q=0.040). 17 metabolites were linked to epilepsy, of these, five remained significant after FDR correction, including 2,3-dihydroxy-5-methylthio-4-pentenoate (OR=0.81, Q=0.009) and 3-ureidopropionate (OR=1.09, Q=0.024). γ-Glutamylvaline showed nominally significant associations with both disorders but in opposite directions (CP: OR=1.25, p=0.040; epilepsy: OR=0.95, p=0.031); neither survived FDR correction. Reverse MR analyses did not support reverse associations for CP (all p>0.05), although genetic liability to epilepsy was associated with two CSF metabolites. Sensitivity analyses did not detect evidence of directional pleiotropy.
These findings provide hypothesis-generating evidence regarding metabolic pathways potentially involved in CP and epilepsy and may inform future experimental and clinical investigations. Independent validation and functional studies are required before clinical application can be considered.

PMID:
42772794
Bibliographic data and abstract were imported from PubMed on 23 Sep 2026.

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