Abstracts

Rationale: The clinical use of levetiracetam (LEV) is limited in a subset of patients by neurobehavioral side effects including irritability and aggression, and more rarely, psychosis. The genetic basis for behavioral difficulty (BD) in response to LEV is entirely unknown. Methods: A genome-wide association study (GWAS) of common single nucleotide polymorphisms (SNPs) and both common and rare copy number variants (CNVs) was conducted on a cohort of chronic epilepsy patients (n=237) retrospectively assessed for BD following exposure to LEV. Patients were classified as cases if LEV was discontinued specifically due to BD, and controls if there was no mention in the patient history of BD after at least one year of continuous LEV treatment. Results: No common SNPs were significantly associated with LEV-related BD after correction for multiple testing. However, the most strongly associated SNP was located in the NRXN1 gene (OR = 5.22, 95%CI: 2.5 - 10.9, p = 8.2 X 10^-5), deletions in which had previously been associated with schizophrenia. Inspection of CNVs in the NRXN1 region revealed that three individuals carried deletions spanning coding exons of NRXN1, and these deletions were exclusive to cases (3/47 vs. 0/190, p = 0.007). Conclusions: These results suggest that NRXN1, which is known to have a strong involvement in risk for schizophrenia, is also associated with LEV-related neurobehavioral side effects. These findings, however, require independent replication, which is an ongoing effort. Additional ongoing studies include targeted sequencing to uncover smaller-scale rare variants affecting antiepileptic drug response as well as shared risk factors between epilepsy and schizophrenia.