Objective: Cognitive impairment is prevalent among individuals with epilepsy, and it is possible that genetic factors can underlie this relationship. Here, we investigated the potential shared genetic basis of common epilepsies and general cognitive ability (COG). Methods: We applied linkage disequilibrium score (LDSC) regression, MiXeR and conjunctional false discovery rate (conjFDR) to analyze different aspects of genetic overlap between COG and epilepsies. We used the largest available genome–wide association study data on COG (n = 269,867) and common epilepsies (n = 27,559 cases, 42,436 controls), including the broad phenotypes ′all epilepsy ′, focal epilepsies and genetic generalized epilepsies (GGE), and as well as specific subtypes. We functionally annotated the identified loci using a variety of biological resources and validated the results in independent samples. Results: Using MiXeR, COG (11.2k variants) was estimated to be almost four times more polygenic than ′all epilepsy′, GGE, juvenile myoclonic epilepsy (JME), and childhood absence epilepsy (CAE) (2.5k — 2.9k variants). The other epilepsy phenotypes were insufficiently powered for analysis. We show extensive genetic overlap between COG and epilepsies with significant negative genetic correlations (-0.23 to -0.04). COG was estimated to share 2.9k variants with both GGE and ′all epilepsy′, and 2.3k variants with both JME and CAE. Using conjFDR, we identified 66 distinct loci shared between COG and epilepsies, including novel associations for GGE (27), ′all epilepsy′ (5), JME (5) and CAE (5). The implicated genes were significantly expressed in multiple brain regions. The results were validated in independent samples (COG: p = 1.0 × 10 ^-14; ′all epilepsy′: p = 5.6 × 10 ^-3). Significance: Our study demonstrates a substantial genetic basis shared between epilepsies and COG and identifies novel overlapping genomic loci. Enhancing our understanding of the relationship between epilepsies and COG may lead to the development of novel comorbidity–targeted epilepsy treatments.

中文翻译：

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揭示常见癫痫和一般认知能力的共同遗传学。

目的：认知障碍在癫痫患者中普遍存在，遗传因素可能是这种关系的基础。在这里，我们研究了常见癫痫和一般认知能力（COG）的潜在共同遗传基础。 方法：我们应用连锁不平衡评分 (LDSC) 回归、MiXeR 和联合错误发现率 (conjFDR) 来分析 COG 和癫痫之间遗传重叠的不同方面。我们使用了关于 COG（ n = 269,867）和常见癫痫（n = 27,559 例，42,436 对照）的最大可用全基因组关联研究数据，包括广泛表型“所有癫痫”、局灶性癫痫和遗传性全身性癫痫 (GGE)，以及特定的亚型。我们使用各种生物资源对识别的位点进行功能注释，并在独立样本中验证结果。结果：使用 MiXeR，估计 COG（11.2k 变异）的多基因性几乎是“所有癫痫”、GGE、青少年肌阵挛性癫痫 (JME) 和儿童失神癫痫 (CAE)（2.5k - 2.9k 变异）的四倍。其他癫痫表型的分析能力不足。我们发现 COG 和癫痫之间存在广泛的遗传重叠，具有显着的负遗传相关性（-0.23 至 -0.04）。据估计，COG 与 GGE 和“所有癫痫”共享 2.9k 个变异，与 JME 和 CAE 共享 2.3k 个变异。使用 conjFDR，我们确定了 COG 和癫痫之间共享的 66 个不同基因座，包括与 GGE (27)、“所有癫痫”(5)、JME (5) 和 CAE (5) 的新关联。相关基因在多个大脑区域显着表达。结果在独立样本中得到验证（COG：p = 1.0 × 10 ^-14；“所有癫痫”：p = 5.6 × 10 ^-3）。意义：我们的研究证明了癫痫和 COG 之间具有共同的重要遗传基础，并确定了新的重叠基因组位点。增强我们对癫痫和 COG 之间关系的理解可能会导致针对癫痫合并症的新型治疗方法的开发。