Abstract
Previous studies have indicated a potential relationship between zinc and epilepsy. The aim of this study is to investigate the causal relationship between zinc, zinc-dependent carbonic anhydrase, and gray matter volume in brain regions enriched with zinc and epilepsy, as well as explore the possible mechanisms by which zinc contributes to epilepsy. First, this study assessed the risk causality between zinc, carbonic anhydrase, and gray matter volume alterations in zinc-enriched brain regions and various subtypes of epilepsy based on Two-sample Mendelian randomization analysis. And then, this study conducted GO/KEGG analysis based on colocalization analysis, MAGMA analysis, lasso regression, random forest model, and XGBoost model. The results of Mendelian randomization analyses showed a causal relationship between zinc, carbonic anhydrase-4, and generalized epilepsy (p = 0.044 , p = 0.010). Additionally, carbonic anhydrase-1 and gray matter volume of the caudate nucleus were found to be associated with epilepsy and focal epilepsy (p = 0.014, p = 0.003 and p = 0.022, p = 0.009). A colocalization relationship was found between epilepsy and focal epilepsy (PP.H4.abf = 97.7e − 2). Meanwhile, the MAGMA analysis indicated that SNPs associated with epilepsy and focal epilepsy were functionally localized to zinc-finger-protein-related genes (p < 1.0e − 5). The genes associated with focal epilepsy were found to have a molecular function of zinc ion binding (FDR = 2.3e − 6). After the onset of epilepsy, the function of the gene whose expression changed in the rats with focal epilepsy was enriched in the biological process of vascular response (FDR = 4.0e − 5). These results revealed mechanism of the increased risk of epilepsy caused by elevated zinc may be related to the increase of zinc ion-dependent carbonic anhydrase or the increase of the volume of zinc-rich caudate gray matter.
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The original data supporting the findings of this study are available in the article/Supplementary material, and further inquiries can be directed to the corresponding author.
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Funding
This work was supported by the Science and Technology Program (Key Research and Development Program) of Gansu Province (Grant/Award Number: 21YF1FA171), the Joint Funds of the National Natural Science Foundation of Gansu Province (Grant/Award Number: 23JRRA1504), the Natural Science Foundation of Gansu Province (Grant/Award Number: 82160262), and the Cuiying Technology Innovation Project of Lanzhou University Second Hospital (Grant/Award Number: CY2023-MS-B03).
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Wang T, Luo D, Liu Y, Li J, and Liu X wrote the main manuscript text. Wang T, Luo D, Zhang R, Zhang N, Chen S, Zhang L, Liu J, and Zhang W prepared all figures of this manuscript. And Wang T is responsible for ensuring that the descriptions are accurate and agreed by all authors. All authors reviewed the manuscript.
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Luo, D., Liu, Y., Li, J. et al. Systematic Analysis of the Relationship Between Elevated Zinc and Epilepsy. J Mol Neurosci 74, 39 (2024). https://doi.org/10.1007/s12031-024-02213-7
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DOI: https://doi.org/10.1007/s12031-024-02213-7