Cerebrospinal fluid metabolites and brain imaging in epilepsy subtypes: Mendelian randomization and multi-omics...

Area of Science:

• Neuroscience
• Genetics
• Biochemistry

Background:

• Epilepsy is a complex neurological disorder with significant genetic underpinnings.
• Observational studies identify associations, but Mendelian randomization (MR) is crucial for establishing causality.
• Multi-omics approaches are vital for exploring genetic influences on epilepsy etiology.

Purpose of the Study:

• To investigate genetically proxied associations among cerebrospinal fluid metabolites, neuroimaging phenotypes, and epilepsy.
• To prioritize candidate genes and potential therapeutic targets for epilepsy.
• To leverage multi-omics data for a comprehensive understanding of epilepsy's genetic basis.

Main Methods:

• Two-sample Mendelian randomization (MR) analyses were conducted using genome-wide association studies, gene expression databases, and UK Biobank data.
• Immune infiltration, transcription factors, and single-nucleotide polymorphism annotation were assessed.
• Single-cell RNA sequencing was utilized for gene localization.

Main Results:

• Significant associations were found between 14 cerebrospinal fluid metabolites and focal epilepsy (11 protective, 3 risk-associated).
• 259 neuroimaging phenotypes demonstrated significant associations with focal epilepsy.
• Top-ranked genes DAB1, ITGA8, and RORA were localized to inhibitory neurons, oligodendrocyte precursor cells, and astrocytes, respectively.

Conclusions:

• Findings reveal cell-specific pathology in epilepsy, impacting inhibitory circuits, myelin integrity, and astrocyte-mediated functions.
• Identified metabolic and structural associations may represent early endophenotypes of epilepsy.
• The study identified a gene-metabolite-imaging feature network implicated in epileptogenesis, offering targets for future research and precision medicine.