Unraveling the shared genetics of common epilepsies and general cognitive ability

IF 2.7 3区医学 Q2 CLINICAL NEUROLOGY Seizure-European Journal of Epilepsy Pub Date : 2024-09-27 DOI:10.1016/j.seizure.2024.09.016

Naz Karadag , Espen Hagen , Alexey A. Shadrin , Dennis van der Meer , Kevin S. O'Connell , Zillur Rahman , Gleda Kutrolli , Nadine Parker , Shahram Bahrami , Vera Fominykh , Kjell Heuser , Erik Taubøll , Torill Ueland , Nils Eiel Steen , Srdjan Djurovic , Anders M. Dale , Oleksandr Frei , Ole A. Andreassen , Olav B. Smeland

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Abstract

Purpose

Cognitive impairment is prevalent among individuals with epilepsy, and increasing evidence indicates that genetic factors can underlie this relationship. However, the extent to which epilepsy subtypes differ in their genetic relationship with cognitive function, and information about the specific genetic variants involved remain largely unknown.

Methods

We investigated the genetic relationship between epilepsies and general cognitive ability (COG) using complementary statistical tools, including linkage disequilibrium score (LDSC) regression, MiXeR and conjunctional false discovery rate (conjFDR). We analyzed 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), as well as specific subtypes. We functionally annotated the identified loci using several 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 MiXeR analysis. We quantified extensive genetic overlap between COG and epilepsy types, but with varying 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 = 3.62 × 10^–7; ‘all epilepsy’: p = 2.58 × 10^–3).

Conclusion

Our study further dissects the substantial genetic basis shared between epilepsies and COG and identifies novel shared loci. An improved understanding of the genetic relationship between epilepsies and COG may lead to the development of novel comorbidity-targeted epilepsy treatments.

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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很普遍，越来越多的证据表明，遗传因素可能是这种关系的基础。然而，癫痫亚型与认知功能的遗传关系在多大程度上存在差异，以及所涉及的特定遗传变异的相关信息在很大程度上仍不为人所知：我们使用互补统计工具，包括连锁不平衡评分（LDSC）回归、MiXeR 和联合误发现率（conjunctional false discovery rate，conjFDR），研究了癫痫与一般认知能力（COG）之间的遗传关系。我们分析了 COG（n = 269,867 例）和常见癫痫（n = 27,559 例，42,436 例对照）的全基因组关联研究数据，包括广义表型 "所有癫痫"、局灶性癫痫和遗传性广泛性癫痫（GGE）以及特定亚型。我们利用多种生物资源对确定的基因座进行了功能注释，并在独立样本中对结果进行了验证：使用 MiXeR 估计，COG（11.2 千个变异）的多基因性几乎是 "所有癫痫"、GGE、幼年肌阵挛性癫痫（JME）和儿童失神性癫痫（CAE）（2.5 千 - 2.9 千个变异）的四倍。其他癫痫表型的 MiXeR 分析动力不足。我们量化了 COG 与癫痫类型之间广泛的遗传重叠，但遗传负相关各不相同（-0.23 至 -0.04）。据估计，COG与GGE和 "所有癫痫 "共享290万个变异，与JME和CAE共享230万个变异。利用 conjFDR，我们确定了 COG 与癫痫之间共有的 66 个不同基因位点，其中包括与 GGE（27 个）、"所有癫痫"（5 个）、JME（5 个）和 CAE（5 个）相关的新基因。相关基因在多个脑区均有显著表达。这些结果在独立样本中得到了验证（COG：p = 3.62 × 10-7；"所有癫痫"：p = 2.58 × 10-3）：结论：我们的研究进一步剖析了癫痫与 COG 之间共享的重要遗传基础，并确定了新的共享基因位点。进一步了解癫痫与 COG 之间的遗传关系可能有助于开发新的以合并症为目标的癫痫治疗方法。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Seizure-European Journal of Epilepsy 医学-临床神经学

CiteScore

5.60

自引率

6.70%

发文量

231

审稿时长

34 days

期刊介绍： Seizure - European Journal of Epilepsy is an international journal owned by Epilepsy Action (the largest member led epilepsy organisation in the UK). It provides a forum for papers on all topics related to epilepsy and seizure disorders.