Contribution of common and rare genetic factors to the etiology of genetic epilepsies and pharmacoresponse

常见和罕见遗传因素对遗传性癫痫病因和药物反应的贡献

• 批准号: 423633757
• 负责人: Dr. Stefan Wolking
• 金额: --
• 依托单位: Centre de Recherche du Centre Hospitalier de lUniversité de Montréal (CRCHUM)
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2019
• 资助国家: 德国
• 起止时间: 2018-12-31 至 2019-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/423633757?language=en
• 关键词: Contribution; common; rare; genetic; factors

Epilepsy affects 0.5 to 1 % of the population. A genetic etiology is common but in many cases still not well understood. For developmental and epileptic encephalopathies (DEEs), severe epilepsy syndromes of childhood, an increasing number monogenic causes has been identified. For the more frequent genetic generalized epilepsies (GGE) that represent about one third of all epilepsies a more complex mode of inheritance has to be assumed. As in other complex genetic disorders, rare and common single nucleotide variants as well as copy number variants have been identified. However, these discoveries account only for a minor proportion of GGEs, so far. Another and more novel field is pharmacogenetics in epilepsy treatment. Pharmacogenetics intends to establish an individualized treatment based on genetic biomarkers. It aims to identify prediction markers for pharmacoresponse or adverse effects. Whereas in other fields, such as oncology, pharmacogenetics take a viable part in prognosis and treatment decisions, discoveries in epilepsy are limited to cutaneous drug reactions. This proposed project pursues two tasks:Task 1) The identification of genetic risk factors for genetic epilepsy syndromes: DEE and GGE. We will evaluate the role of common genetic variants using the polygenic transmission disequilibrium technique (pTDT). pTDT works under the assumption that epilepsy patients harbor a higher genetic load for a variety of neuro-psychiatric disorders. This method has been recently described for other complex genetic disorders such as autism spectrum disorder and migraine. This approach is based on the analysis of trio families (healthy parents, affected child) and incorporates polygenic risk scores (PRS) to assess the common variant predisposition for a specific trait. To create PRS discovery cohorts we will use summary statistics from epilepsy cohorts (ILAE meta-analyses 2014 and 2018) and from publicly available cohorts with other neuropsychiatric disorders. For this analysis 600 GGE trios and about 340 DEE trios will be at our disposition.Task 2) The identification of genetic biomarkers for pharmacoresponse to specific antiepileptic drugs (AEDs). We will undertake candidate gene analyses, gene set analyses as well as structural variant analyses for cohorts of several hundreds of patients for the AEDs lamotrigine, valproate and levetiracetam. We expect to identify possible variants in genes that are either targets of antiepileptic drugs or that are involved in pharmacokinetics, such as drug transporters or genes involved in drug metabolization. For both tasks, sufficient numbers of patients with genotype (GWAS) and/ or whole exome data are available that derive from previous collaboration projects. This project will be important to further strengthen the cooperation between the groups in Montreal and Tübingen and to ultimately establish a clinical, genetical and bioinformatical work group in Tübingen.

癫痫影响0.5%至1%的人口。遗传病因是常见的，但在许多情况下仍然没有很好地理解。对于发育性和癫痫性脑病（DEE），儿童严重癫痫综合征，越来越多的单基因原因已被确定。对于更频繁的遗传性全身性癫痫（GGE），代表约三分之一的所有癫痫，一个更复杂的遗传模式，必须假设。与其他复杂的遗传性疾病一样，已经鉴定出罕见和常见的单核苷酸变异以及拷贝数变异。然而，到目前为止，这些发现仅占GGE的一小部分。另一个更新颖的领域是癫痫治疗的药物遗传学。药物遗传学旨在建立基于遗传生物标志物的个体化治疗。其目的是确定药物反应或不良反应的预测标志物。而在其他领域，如肿瘤学，药物遗传学在预后和治疗决策中发挥了可行的作用，癫痫的发现仅限于皮肤药物反应。该项目主要有两个任务：任务1）识别遗传性癫痫综合征的遗传风险因素：DEE和GGE。我们将使用多基因传递不平衡技术（pTDT）评估常见遗传变异的作用。pTDT的工作假设是癫痫患者对各种神经精神疾病具有更高的遗传负荷。这种方法最近被描述用于其他复杂的遗传疾病，如自闭症谱系障碍和偏头痛。该方法基于对三人家庭（健康父母，受影响儿童）的分析，并结合多基因风险评分（PRS）来评估特定性状的常见变异倾向。为了创建PRS发现队列，我们将使用癫痫队列（ILAE荟萃分析2014和2018）和其他神经精神疾病的公开队列的汇总统计量。对于这项分析，600个GGE三人组和大约340个DEE三人组将在我们的处置。任务2）识别遗传生物标志物的药效反应，以特定的抗癫痫药物（AED）。我们将进行候选基因分析、基因集分析以及数百例AED拉莫三嗪、丙戊酸盐和左乙拉西坦患者队列的结构变异分析。我们希望确定可能的变异基因，无论是抗癫痫药物的目标或参与药物代谢，如药物转运蛋白或基因参与药物代谢。对于这两项任务，有足够数量的患者基因型（GWAS）和/或整个外显子组数据，来自以前的合作项目。该项目将进一步加强蒙特利尔和蒂宾根两个小组之间的合作，并最终在蒂宾根建立一个临床、遗传学和生物信息学工作组。

项目成果

Testing association of rare genetic variants with resistance to three common antiseizure medications

• DOI: 10.1111/epi.16467
• 发表时间: 2020-04-01
• 期刊: EPILEPSIA
• 影响因子: 5.6
• 作者: Wolking, Stefan;Moreau, Claudia;Lerche, Holger
• 通讯作者: Lerche, Holger

Pharmacoresponse in genetic generalized epilepsy: a genome-wide association study.

• DOI: 10.2217/pgs-2019-0179
• 发表时间: 2020-04
• 期刊: Pharmacogenomics
• 影响因子: 2.1
• 作者: S. Wolking;H. Schulz;A. Nies;M. McCormack;E. Schaeffeler;P. Auce;A. Avbersek;F. Becker;K. Klein;M. Krenn;R. Møller;M. Nikanorova;S. Weckhuysen;Epi4K Consortium;G. Cavalleri;N. Delanty;C. Depondt;Michael R. Johnson;B. Koeleman;W. Kunz;A. Marson;Josemir W Sander;G. Sills;P. Striano;F. Zara;F. Zimprich;Y. Weber;R. Krause;S. Sisodiya;M. Schwab;T. Sander;H. Lerche