1 in 26 people in the US have a diagnosis of epilepsy, characterized by seizures resulting from abnormal electrical discharges in the brain. These seizures have heterogeneous physical manifestations (convulsions, sensory disturbances, or loss of consciousness) and are observed at markedly increased frequencies in persons with psychiatric and neurodevelopmental disorders. At least a third of persons with epilepsy experience additional seizures whilst on treatment. We do not understand the pathogenesis of common forms of epilepsy not due to obvious injury or severe mutations; whether different forms of epilepsy are driven by different pathogenic mechanisms; or whether these mechanisms are (partly) shared with other diseases and thus drive the observed comorbidity. This limits clinical management options, accurate prognosis including the likelihood of comorbid psychiatric disease, and development of new therapies. Epidemiological studies of epilepsy could uncover outcome predictors, and human genetic studies could uncover both causal genes and whether these also contribute risk of other diseases; these results would provide a substrate both for discovering pathogenic mechanisms and for predicting patient outcomes. However, these activities require large cohorts with both lifelong medical data and DNA material, which are not available in the US. We have a unique opportunity to overcome this barrier using the population resources available in Denmark: we can retrieve and genotype DNA from neonatal bloodspots for ~12,000 persons with epilepsy via the Danish National Hospital Register, and match these to life-long clinical data and life events. By incorporating data from previous genetic studies of epilepsy and of neuropsychiatric disease, and by using our state-of-the-art methods to identify causal genes from such data, we can thus (1) perform a well-powered genetic study in epilepsy and identify causal genes; (2) test and validate predictors of outcomes, including comorbid psychiatric disease in persons with epilepsy, and whether they are causal; (3) establish if comorbid psychiatric disease shares heritability, and thus a pathological basis, with epilepsy. Specifically, we will: 1. Identify genetic variants predisposing to epilepsy and the genes they affect. Use the heritability information in genome-wide variation to assess if epilepsy subtypes are driven by the same pathogenic mechanisms, and if these are shared with comorbid psychiatric disease. 2. Identify outcome predictors for persons with epilepsy, and their genetic determinants. These studies will uncover genes driving epilepsy pathogenesis, and establish if the subtypes of common, complex epilepsy share these mechanisms. Our findings will be crucial to any future preventive or intervention strategies, as they will enable clinicians to predict the likelihood of comorbid psychiatric disease in persons with epilepsy at the time of diagnosis, and suggest targets for developing new anti-seizure medications.
1 in 26 people in the US have a diagnosis of epilepsy, a third of whom do not respond to medication; persons with epilepsy are also at much higher risk of developing a psychiatric disorder. To understand the root causes of epilepsy, if the different forms of the disease share these causes, and if these causes are also shared with secondary psychiatric diseases, we will obtain DNA samples and life-long clinical records for all persons with epilepsy in Denmark via their integrated hospital records and biomaterial collection. We will look for genes that drive risk to epilepsy, establish if the same genetic risk factors drive different forms of disease and/or psychiatric disease, and look for events that predict medical outcomes, including the development of psychiatric disease.