Focal epilepsy (FE) is clinically highly heterogeneous. It has been shown recently that not only rare but also a subset of common genetic variants confer risk for FE. The relatively modest power of genetic studies in FE suggests a high genetic heterogeneity of FE when grouped as one disorder. We hypothesize that the clinical heterogeneity of FE is correlated with genetic heterogeneity on a common risk variant level. To test the hypothesis, we used an FE polygenic risk score “FE‐PRS” that combines small effect sizes of thousands of common variants from the largest FE‐GWAS (genome‐wide association study) into a single measure. We grouped 414 individuals with FE according to common clinical features into subgroups, either by one feature at a time or by all features combined in a cluster analysis. We examined their association with FE‐PRS compared to 20 435 matched population controls and observed heterogeneous FE‐PRS burden among the subgroups. The highest phenotypic variance explained by FE‐PRS was identified in a cluster analysis–defined FE subgroup where all individuals had unknown etiologies and psychiatric comorbidities, and the majority had early onset seizures. Our results indicate that genetic factors associated with FE have differential burden among FE subtypes. Future studies using better‐powered FE‐PRS might have clinical utility.

中文翻译：

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局灶性癫痫的多基因风险异质性

局灶性癫痫 (FE) 在临床上具有高度异质性。最近已经表明，不仅罕见而且一部分常见的遗传变异会导致 FE 风险。FE 中遗传研究的相对温和的力量表明，当归为一种疾病时，FE 具有高度的遗传异质性。我们假设 FE 的临床异质性与常见风险变异水平上的遗传异质性相关。为了验证这一假设，我们使用了 FE 多基因风险评分“FE-PRS”，该评分将来自最大 FE-GWAS（全基因组关联研究）的数千种常见变异的小效应量组合成单一测量。我们根据常见的临床特征将 414 名患有 FE 的个体分为亚组，要么一次一个特征，要么通过聚类分析中的所有特征组合。与 20 435 名匹配的人群对照相比，我们检查了它们与 FE-PRS 的关联，并观察到亚组之间的异质 FE-PRS 负担。由 FE-PRS 解释的最高表型变异是在聚类分析定义的 FE 亚组中确定的，其中所有个体都有未知的病因和精神共病，并且大多数有早发性癫痫发作。我们的结果表明，与 FE 相关的遗传因素在 FE 亚型之间具有不同的负担。未来使用动力更好的 FE-PRS 的研究可能具有临床效用。并且大多数有早发性癫痫发作。我们的结果表明，与 FE 相关的遗传因素在 FE 亚型之间具有不同的负担。未来使用动力更好的 FE-PRS 的研究可能具有临床效用。并且大多数有早发性癫痫发作。我们的结果表明，与 FE 相关的遗传因素在 FE 亚型之间具有不同的负担。未来使用动力更好的 FE-PRS 的研究可能具有临床效用。