Wu Zhanshen, Zhao Yang, Zhang Bo, Li Yanyan
Department of Pharmacy, the Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou 450015, China.
Department of Pharmacy, the Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou 450015, China.
Epilepsy Behav. 2025 Mar;164:110253. doi: 10.1016/j.yebeh.2024.110253. Epub 2025 Jan 16.
The study aimed to investigate the causal relationship between serum 25-hydroxyvitamin D (25(OH)D) levels and epilepsy using Mendelian randomization (MR), thereby addressing confounding and reverse causality issues in observational studies.
We employed a two-sample bidirectional MR design utilizing summary-level data from the IEU OpenGWAS project. Serum 25(OH)D levels were analyzed using the publicly available dataset ebi-a-GCST90000618, which included 496,946 European samples and 68,960,93 SNPs. Data on epilepsy were obtained from ebi-a-GCST90018840, comprising 458,310 samples, including 4,382 epilepsy patients and 453,928 controls. To identify instrumental variables (IVs), we applied a significance threshold of P < 5e-8 for serum 25(OH)D levels as the exposure and P < 5e-6 for epilepsy as the exposure. IVs were required to demonstrate an r < 0.001 linkage disequilibrium and an F-statistic greater than 10. The MR analysis utilized five methods: inverse variance weighted (IVW), weighted median, MR-Egger, weighted mode, and simple mode, assessing causal relationships between serum 25(OH)D levels and epilepsy. Robustness checks included heterogeneity tests, leave-one-out sensitivity analyses, and assessments for horizontal pleiotropy.
Both directions of the MR analysis revealed no genetic correlation between serum 25(OH)D levels and epilepsy.
Our findings, supported by robust IV screening and consistent results across multiple MR methods, indicate a lack of causal relationship between serum 25(OH)D levels and epilepsy. These results suggest that while vitamin D plays a role in the nervous system, its relationship to epilepsy may not be direct, thus highlighting the need for further investigation in future studies.
本研究旨在利用孟德尔随机化（MR）研究血清25-羟基维生素D（25(OH)D）水平与癫痫之间的因果关系，从而解决观察性研究中的混杂和反向因果关系问题。
我们采用了两样本双向MR设计，利用来自IEU OpenGWAS项目的汇总水平数据。使用公开可用的数据集ebi-a-GCST90000618分析血清25(OH)D水平，该数据集包括496,946个欧洲样本和68,960,93个单核苷酸多态性（SNP）。癫痫数据来自ebi-a-GCST90018840，包括458,310个样本，其中有4,382名癫痫患者和453,928名对照。为了识别工具变量（IV），我们将血清25(OH)D水平作为暴露因素时的显著性阈值设为P < 5e-8，将癫痫作为暴露因素时的显著性阈值设为P < 5e-6。IV需要显示r < 0.001的连锁不平衡和大于10的F统计量。MR分析采用了五种方法：逆方差加权（IVW）、加权中位数、MR-Egger、加权模式和简单模式，以评估血清25(OH)D水平与癫痫之间的因果关系。稳健性检验包括异质性检验、留一法敏感性分析和水平多效性评估。
MR分析的两个方向均显示血清25(OH)D水平与癫痫之间无遗传相关性。
我们的研究结果得到了稳健的IV筛选和多种MR方法一致结果的支持，表明血清25(OH)D水平与癫痫之间缺乏因果关系。这些结果表明，虽然维生素D在神经系统中发挥作用，但其与癫痫的关系可能不是直接的，因此凸显了在未来研究中进一步调查的必要性。
