Yu Cheng, Jiang Shijiu, Lv Bingjie, Deng Xuejun, Xu Da
Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Epilepsy Behav. 2024 Dec;161:110140. doi: 10.1016/j.yebeh.2024.110140. Epub 2024 Nov 13.
Observational studies suggest that hypertension and epilepsy have a high co-occurrence, and antihypertensive medications may have impacts on the prevention and treatment of epilepsy. However, the directionality of causation between them is elusive.
By leveraging genome-wide association studies (GWAS) summary data of each trait, we firstly performed bidirectional univariate Mendelian randomization (UVMR) to assess the strength and direction of the associations between pairs of traits, then multivariate MR (MVMR) was conducted to adjust for potential confounders in causalities. Cochran's Q statistics, leave-one-out analysis, MR-Egger regression and MR-Pleiotropy Residual Sum and Outlier methods (MR-PRESSO) were employed to evaluate the robustness of the results. Drug target MR was proceeded to assess the association between five classes of first-line antihypertensive medications and epilepsy. Specifically, single nucleotide polymorphisms (SNPs) extracted from GWAS data on systolic blood pressure (SBP)/diastolic blood pressure (DBP), along with expression quantitative trait loci (eQTL) were utilized as proxies for antihypertensive medications, respectively.
Forward UVMR results provided evidence that genetically predicted blood pressure traits and hypertension have causal effects on epilepsy, while reverse UVMR indicated no causal impacts of epilepsy on blood pressure traits or hypertension. The sensitivity analysis results were robust. The causalities between DBP, hypertension and epilepsy remained remarkable after adjustment by MVMR. Inverse-variance-weighted MR (IVW-MR) yielded evidence of positive association only between Beta-Blockers target genes based on DBP GWAS screening and epilepsy. Summary-data-based MR (SMR) identified a positive correlation between Beta-Blockers target gene ADRA1D and epilepsy risk.
Hypertension has a causal effect on epilepsy and managing DBP in patients with hypertension through Beta-Blockers may help prevent epilepsy.
观察性研究表明，高血压和癫痫的共现率很高，抗高血压药物可能对癫痫的预防和治疗有影响。然而，它们之间因果关系的方向性尚不清楚。
通过利用每种性状的全基因组关联研究（GWAS）汇总数据，我们首先进行双向单变量孟德尔随机化（UVMR）以评估性状对之间关联的强度和方向，然后进行多变量MR（MVMR）以调整因果关系中的潜在混杂因素。采用 Cochr an's Q统计量、留一法分析、MR-Egger回归和MR-多效性残差和离群值方法（MR-PRESSO）来评估结果的稳健性。进行药物靶点MR以评估五类一线抗高血压药物与癫痫之间的关联。具体而言，从收缩压（SBP）/舒张压（DBP）的GWAS数据中提取的单核苷酸多态性（SNP）以及表达数量性状位点（eQTL）分别用作抗高血压药物的替代指标。
正向UVMR结果提供了证据，表明基因预测的血压性状和高血压对癫痫有因果影响，而反向UVMR表明癫痫对血压性状或高血压没有因果影响。敏感性分析结果稳健。MVMR调整后，DBP、高血压和癫痫之间的因果关系仍然显著。基于DBP的GWAS筛选，逆方差加权MR（IVW-MR）仅在β受体阻滞剂靶基因与癫痫之间产生了正相关的证据。基于汇总数据的MR（SMR）确定了β受体阻滞剂靶基因ADRA1D与癫痫风险之间存在正相关。
高血压对癫痫有因果影响，通过β受体阻滞剂控制高血压患者的DBP可能有助于预防癫痫。
