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

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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.