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

癫痫影响0.5%至1%的人口。遗传病因是常见的，但在许多情况下仍不清楚。对于发育性和癫痫性脑病（dee），儿童时期的严重癫痫综合征，已经确定了越来越多的单基因原因。对于更常见的遗传性广泛性癫痫（GGE），约占所有癫痫的三分之一，必须假设更复杂的遗传模式。与其他复杂的遗传疾病一样，已经发现了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，这些发现只占gge的一小部分。另一个更新颖的领域是药物遗传学在癫痫治疗中的应用。药物遗传学旨在建立一种基于遗传生物标志物的个体化治疗。目的是确定药物反应或不良反应的预测标记。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着重要作用，癫痫的发现仅限于皮肤药物反应。本课题主要开展两项工作：任务1)确定遗传性癫痫综合征的遗传危险因素：DEE和GGE。我们将利用多基因传递不平衡技术（pTDT）评估常见遗传变异的作用。pTDT的工作原理是假设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。该方法基于对三个家庭（健康父母和患病儿童）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易感性。为了创建PRS发现队列，我们将使用癫痫队列（ILAE荟萃分析2014年和2018年）和其他神经精神疾病公开队列的汇总统计数据。对于这个分析，600个GGE三重奏和约340个DEE三重奏将在我们的处置。任务2)特异性抗癫痫药物（aed）药物反应的遗传生物标志物鉴定。我们将对数百名aed患者进行候选基因分析、基因集分析以及结构变异分析。这些患者使用拉莫三嗪、丙戊酸酯和左乙拉西坦。我们希望确定抗癫痫药物靶点基因或参与药代动力学的基因的可能变异，如药物转运体或参与药物代谢的基因。对于这两项任务，从以前的合作项目中获得了足够数量的基因型（GWAS）和/或全外显子组数据。该项目将进一步加强蒙特利尔和<s:1>宾根研究组之间的合作，并最终在<s:1>宾根建立一个临床、遗传和生物信息学工作组。

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.