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.