We are investigating the genetic relationship between epilepsy and depression. Depression is the most common comorbid condition in epilepsy, affecting between 20-55% of patients with refractory epilepsy and 3-9% of patients with well-controlled seizures. The cause of this comorbidity is unknown. We are conducting a series of genetic epidemiologic studies to test the hypothesis that the comorbidity is due, in part, to a shared genetic susceptibility. Identifying a shared genetic susceptibility will help identify individuals at high risk for both disorders, allow for early intervention, and increase an understanding of pathogenesis. In the first of these studies, we attempted to distinguish between the effects of LGI1 mutations, a known cause for a rare type of epilepsy, and the effects of epilepsy or its treatment (e.g., reactive or iatrogenic effects). We compared affected and unaffected carriers of LGI1 mutations with non-carriers from within the same families. Results of this study did not support the shared etiology hypothesis, at least for this subtype of epilepsy (Heiman et al, 2008). Other studies are still in the data collection phase.