Department of Neurology, University of Gothenburg, Göteborg, Sweden (S.C.-T., C.A.R., S.M., L.H.S., A.d.H., L.J.H., E.J.G., K.N.S., J.A.K., G.J.F., N.K.M.).
Department of Clinical Neuroscience, University of Gothenburg, Göteborg, Sweden (J.Z.).
Stroke. 2024 Dec;55(12):2835-2843. doi: 10.1161/STROKEAHA.124.047459. Epub 2024 Nov 6.
Epilepsy is highly heritable, with numerous known genetic risk loci. However, the genetic predisposition's role in poststroke epilepsy (PSE) remains understudied. This study assesses whether a higher genetic predisposition to epilepsy raises poststroke survivor's risk of PSE.
We conducted a case-control genetic association study nested within the UK Biobank, a large UK-based prospective cohort. Our exposures of interest were 2 distinct polygenic risk scores-generalized and focal epilepsy-modeled as deciles and constructed using genetic variants identified in the latest International League Against Epilepsy genome-wide association study meta-analysis. We aimed to evaluate the association between these polygenic risk scores and their corresponding subtype of PSE-generalized and focal. In sensitivity analyses, we evaluated participants of European ancestry separately and considered focal and generalized epilepsy outcomes in participants without a history of stroke. In secondary analyses, we evaluated the polygenic risk of PSE by stroke subtype (ischemic, hemorrhagic, or any stroke). Multivariable logistic regression models were fitted, adjusting for age, sex, genetic ancestry, and the first 5 principal genetic components.
Among 17 549 UK Biobank stroke survivors with available genetic information (mean age, 61; 43% female), 185 (1%) developed generalized PSE, while 124 (0.7%) developed focal PSE. Multivariable logistic regression results showed that, when compared against the lowest decile, participants within the highest PRS decile for generalized PSE had 5-fold higher odds of developing generalized PSE (OR, 5.05 [95% CI, 2.37-12.5]; trend<0.001). Similarly, when compared against the lowest decile, participants within the highest polygenic risk score decile for focal PSE had 3-fold higher odds of developing focal PSE (OR, 3.20; [5% CI, 1.25-9.82]; trend=0.024). Sensitivity analyses among participants of European ancestry yielded similar results.
Our findings suggest that, like other forms of epilepsy, genetic predisposition plays an essential role in PSE. These results underscore the need for future studies to elucidate the mechanisms underlying PSE development and to identify novel therapeutic avenues.
癫痫具有高度遗传性，存在许多已知的遗传风险位点。然而，遗传易感性在卒中后癫痫（PSE）中的作用仍研究不足。本研究评估了更高的癫痫遗传易感性是否会增加卒中幸存者发生 PSE 的风险。
我们进行了一项嵌套于英国生物库（UK Biobank）的病例对照遗传关联研究，这是一项大型英国前瞻性队列研究。我们的暴露因素为两种不同的多基因风险评分-广义癫痫和局灶性癫痫-以十分位数的形式建模，并使用最新的国际癫痫联盟全基因组关联研究荟萃分析中鉴定的遗传变异进行构建。我们旨在评估这些多基因风险评分与它们相应的 PSE 广义和局灶亚型之间的关联。在敏感性分析中，我们分别评估了欧洲血统的参与者，并考虑了没有卒中史的参与者中的局灶性和广义癫痫结局。在次要分析中，我们根据卒中亚型（缺血性、出血性或任何卒中）评估了 PSE 的多基因风险。使用多变量逻辑回归模型进行拟合，调整了年龄、性别、遗传祖源和前 5 个主要遗传成分。
在 17549 名有可用遗传信息的 UK Biobank 卒中幸存者中（平均年龄 61 岁，43%为女性），185 名（1%）发生了广义 PSE，而 124 名（0.7%）发生了局灶性 PSE。多变量逻辑回归结果显示，与最低十分位数相比，广义 PSE 最高 PRS 十分位数的参与者发生广义 PSE 的可能性高 5 倍（OR，5.05[95%CI，2.37-12.5]；趋势<0.001）。同样，与最低十分位数相比，局灶性 PSE 最高多基因风险评分十分位数的参与者发生局灶性 PSE 的可能性高 3 倍（OR，3.20[5%CI，1.25-9.82]；趋势=0.024）。在欧洲血统的参与者中进行的敏感性分析得出了类似的结果。
我们的研究结果表明，与其他形式的癫痫一样，遗传易感性在 PSE 中起着至关重要的作用。这些结果强调了需要进一步研究阐明 PSE 发生发展的机制，并确定新的治疗途径。
