偏头痛与癫痫：一项两样本孟德尔随机化研究

doi:10.3877/cma.j.issn.2095-123X.2026.02.002

目的

利用两样本孟德尔随机化（MR）研究方法探讨偏头痛与癫痫发生之间的关系。

方法

从公开的全基因组关联分析（GWAS）数据库中获取偏头痛与癫痫的单核苷酸多态性（SNP），筛选有效的SNP作为工具变量，采用逆方差加权法（IVW）、加权中位数法、MR-Egger回归法、加权众数法及简单模型法进行MR分析，并采用Cochran's Q检验、MR-Egger回归法、漏斗图和留一法进行敏感性分析，评估结果的稳健性。

结果

共筛选出13个符合MR假设的SNPs。5种MR方法的整体效果方向一致，其中以IVW结果最为显著。IVW结果显示，偏头痛与癫痫呈正相关(OR=1.216，95%CI：1.046~1.414，P=0.011)。多种敏感性分析显示研究不存在异质性（P=0.120）和水平多效性（P=0.472），说明结果具有稳健性。

结论

合并偏头痛会增加癫痫的发生风险，应在疾病早期预防和干预癫痫的发生。

关键词: 癫痫, 偏头痛, 孟德尔随机化

Objective

To explore the correlation between migraine and epilepsy using a two sample Mendelian randomization (MR) study method.

Methods

Single nucleotide polymorphism (SNP) information of two samples was obtained from publicly available genome-wide association study (GWAS) databases, and suitable SNPs were selected as instrumental variables. Five methods for MR analysis were employed, including inverse variance weighted (IVW), weighted median estimator (WME), MR-Egger regression, weighted mode, and simple median. Additionally, Cochran's Q test, MR-Egger regression method, funnel plot, and leave-one-out method were used for sensitivity analysis to evaluate the robustness of the results.

Results

This study identified 13 SNPs that satisfied the MR hypothesis. Using the IVW method, it was found that migraine patients have an increased risk of developing epilepsy (OR=1.216, 95%CI: 1.046-1.414, P=0.011), indicating a positive correlation between migraine and epilepsy. Multiple sensitivity analyses showed no heterogeneity (P=0.120) or horizontal pleiotropy (P=0.472) in the study, indicating the robustness of the results.

Conclusions

Comorbid migraine increases the risk of epilepsy, and early prevention and intervention should be implemented to reduce the incidence of epilepsy.

Key words: Epilepsy, Migraine, Mendelian randomization

表1 两样本MR研究GWAS数据库中的偏头痛和癫痫简要信息

Tab.1 Brief information of migraine and epilepsy in the GWAS database for two sample MR analysis

疾病	GWAS ID	样本量	人群	年份	病例数	对照数	SNPs数量
偏头痛	finn-b-G6_MIGRAINE	184 654	欧洲人	2021年	8 547	176 107	16 380 367
癫痫	finn-b-G6_EPLEPSY	182 367	欧洲人	2021年	6 260	176 107	16 380 349

表1 两样本MR研究GWAS数据库中的偏头痛和癫痫简要信息

Tab.1 Brief information of migraine and epilepsy in the GWAS database for two sample MR analysis

疾病	GWAS ID	样本量	人群	年份	病例数	对照数	SNPs数量
偏头痛	finn-b-G6_MIGRAINE	184 654	欧洲人	2021年	8 547	176 107	16 380 367
癫痫	finn-b-G6_EPLEPSY	182 367	欧洲人	2021年	6 260	176 107	16 380 349

图1 MR研究设计流程图SNP：单核苷酸多态性；MR：孟德尔随机化

Fig.1 MR research design flowchart

表2 与暴露有关的SNPs基本信息

Tab.2 Basic information on SNPs related to exposure

SNP	效应等位基因	其他等位基因	等位基因效应大小	等位基因效应位点频率	标准误	P值
rs10770255	T	A	0.144 3	0.075 09	0.031 4	<0.001
rs113409543	G	C	-0.642 9	0.004 584	0.133 1	<0.001
rs1144709	T	C	-0.095 7	0.250 2	0.019 3	<0.001
rs12828811	G	A	-0.110 5	0.145 2	0.023 7	<0.001
rs138931689	A	G	0.197 0	0.040 63	0.043 1	<0.001
rs143370621	G	A	-0.186 8	0.046 31	0.039 6	<0.001
rs145281382	T	C	0.175 7	0.051 62	0.037 3	<0.001
rs2301798	T	C	-0.177 3	0.062 35	0.034 6	<0.001
rs3003958	A	G	0.088 4	0.330 2	0.017 6	<0.001
rs35877876	T	C	0.198 4	0.046 93	0.039 5	<0.001
rs4849052	C	T	-0.329 8	0.983 4	0.066 0	<0.001
rs7398375	G	C	0.091 2	0.332 5	0.017 8	<0.001
rs9349379	G	A	-0.092 1	0.451 1	0.016 6	<0.001

表2 与暴露有关的SNPs基本信息

Tab.2 Basic information on SNPs related to exposure

SNP	效应等位基因	其他等位基因	等位基因效应大小	等位基因效应位点频率	标准误	P值
rs10770255	T	A	0.144 3	0.075 09	0.031 4	<0.001
rs113409543	G	C	-0.642 9	0.004 584	0.133 1	<0.001
rs1144709	T	C	-0.095 7	0.250 2	0.019 3	<0.001
rs12828811	G	A	-0.110 5	0.145 2	0.023 7	<0.001
rs138931689	A	G	0.197 0	0.040 63	0.043 1	<0.001
rs143370621	G	A	-0.186 8	0.046 31	0.039 6	<0.001
rs145281382	T	C	0.175 7	0.051 62	0.037 3	<0.001
rs2301798	T	C	-0.177 3	0.062 35	0.034 6	<0.001
rs3003958	A	G	0.088 4	0.330 2	0.017 6	<0.001
rs35877876	T	C	0.198 4	0.046 93	0.039 5	<0.001
rs4849052	C	T	-0.329 8	0.983 4	0.066 0	<0.001
rs7398375	G	C	0.091 2	0.332 5	0.017 8	<0.001
rs9349379	G	A	-0.092 1	0.451 1	0.016 6	<0.001

图2 偏头痛与癫痫的MR分析森林图IVW汇总：菱形位于无效应线右侧，CI不跨越0，提示暴露增加时会显著升高结局风险，即偏头痛患者发生癫痫的风险增加；IVW：逆方差加权法；MR：孟德尔随机化

Fig.2 Mendelian randomization analysis forest map of migraine and epilepsy

图3 偏头痛对癫痫的MR分析散点图5种MR方法回归斜率为正，提示暴露增加时会显著升高结局风险，即偏头痛患者发生癫痫的风险增加；MR：孟德尔随机化；SNP：单核苷酸多态性

Fig.3 Mendelian randomization analysis scatter plot of migraine on epilepsy

表3 偏头痛对癫痫的MR分析结果

Tab.3 MR analysis results of migraine on epilepsy

暴露	结局	SNP数量	MR方法	OR值	95%CI	P值	异质性检验P值	水平多效性检验P值
			MR-Egger回归法	1.383	0.954~2.007	0.115
			逆方差加权法	1.216	1.046~1.414	0.011
偏头痛	癫痫	13	加权众数法	1.162	0.884~1.527	0.303	0.120	0.472
			简单模型法	1.174	0.869~1.585	0.317
			加权中位数法	1.180	0.994~1.403	0.059

表3 偏头痛对癫痫的MR分析结果

Tab.3 MR analysis results of migraine on epilepsy

暴露	结局	SNP数量	MR方法	OR值	95%CI	P值	异质性检验P值	水平多效性检验P值
			MR-Egger回归法	1.383	0.954~2.007	0.115
			逆方差加权法	1.216	1.046~1.414	0.011
偏头痛	癫痫	13	加权众数法	1.162	0.884~1.527	0.303	0.120	0.472
			简单模型法	1.174	0.869~1.585	0.317
			加权中位数法	1.180	0.994~1.403	0.059

图4 偏头痛对癫痫的MR分析漏斗图MR：孟德尔随机化；SNP：单核苷酸多态性

Fig.4 Mendelian randomization analysis funnel plot of migraine on epilepsy

图5 偏头痛与癫痫因果关联的留一法敏感性分析逐一剔除各SNPs后，所有留一法效应量在原始效应值附近波动，置信区间均包含原效应值，故结果稳定，无单个SNP主导效应；SNP：单核苷酸多态性；MR：孟德尔随机化

Fig.5 Leave-one-out sensitivity analysis of the causal effect of migraine on epilepsyc

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Migraine and epilepsy disease: a two sample Mendelian randomization study

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Migraine and epilepsy disease: a two sample Mendelian randomization study