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Metabolomic determinants of cerebral microvascular pathology: Mendelian randomization evidence from plasma metabolites

Articles in Press

Document Type : Original Article

Authors

1 General Hospital of Ningxia Medical University

2 Yinchuan Maternal and Child Health Hospital

3 Second Affiliated Hospital of Zhejiang University School of Medicine

Abstract

Background: This study investigates the associations between 1400 plasma metabolite traits, including 1091 measured metabolites and 309 metabolite ratios, and ten cerebral small vessel disease (CSVD) phenotypes, including brain microbleeds (BMB), intracerebral hemorrhage (ICH), lacunar stroke, and magnetic resonance imaging (MRI)-derived markers.
Methods: We performed two-sample Mendelian randomization (MR) using summary-level genome-wide association study (GWAS) data on plasma metabolites from the National Human Genome Research Institute-European Bioinformatics Institute GWAS (NHGRI-EBI GWAS) catalog. Causal effects were estimated using inverse-variance weighted (IVW), weighted median (WM), and MR-Egger methods, with false discovery rate (FDR) correction. Pleiotropy and heterogeneity were evaluated to assess robustness.
Results: Forty-eight metabolites showed significant associations with at least one CSVD phenotype after stepwise MR filtering. Effect estimates were reported as odds ratios (ORs) for binary CSVD outcomes and as β coefficients for continuous MRI-derived traits. 
For log-transformed normalized white matter hyperintensity (logWMHnorm), 2-hydroxy-4-(methylthio)butanoic acid showed a positive association with white matter hyperintensity (WMH) volume [β = 0.040, 95% confidence interval (CI): 0.006‒0.074; P = 0.020]. For first principal component of fractional anisotropy (PC1_FA), 13 metabolites showed associations with fractional anisotropy (FA)-derived white matter microstructure, with β coefficients ranging from −0.246 to 0.427. For first principal component of mean diffusivity (PC1_MD), 12 metabolites showed associations with mean diffusivity (MD)-derived white matter microstructure, with β coefficients ranging from −0.382 to 0.297. Heterogeneity or potential horizontal pleiotropy was observed in a subset of associations, supporting cautious interpretation.
Conclusion: This study provides MR-based genetic evidence consistent with potential effects of specific plasma metabolites on CSVD phenotypes. These findings highlight metabolomic signatures across heterogeneous CSVD phenotypes and may help prioritize metabolic pathways for future mechanistic validation.

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Current Journal of Neurology

Articles in Press, Accepted Manuscript
Available Online from 02 September 2026
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