Role of Common Genetic Variants for Drug-Resistance to Specific Anti-Seizure Medications
Stefan Wolking, Ciarán Campbell, Caragh P. Stapleton, Mark McCormack, Norman Delanty, Chantal Depondt, Michael R. Johnson, Bobby P.C. Koeleman, Roland Krause, Wolfram S. Kunz, Anthony G Marson, Josemir W. Sander, Graeme J. Sills, Pasquale Striano, Federico Zara, Sanjay M. Sisodiya, Gianpiero L. Cavalleri, Holger Lerche
Abstract
Objective: Resistance to anti-seizure medications (ASMs) presents a significant hurdle in the treatment of people with epilepsy. Genetic markers for resistance to individual ASMs could support clinicians to make better-informed choices for their patients. In this study, we aimed to elucidate whether the response to individual ASMs was associated with common genetic variation. Methods: A cohort of 3,649 individuals of European descent with epilepsy was deeply phenotyped and underwent single nucleotide polymorphism (SNP)-genotyping. We conducted genome-wide association analyses (GWASs) on responders to specific ASMs or groups of functionally related ASMs, using non-responders as controls. We performed a polygenic risk score (PRS) analyses based on risk variants for epilepsy and neuropsychiatric disorders and ASM resistance itself to delineate the polygenic burden of ASM-specific drug resistance. Results: We identified several potential regions of interest but did not detect genome-wide significant loci for ASM-specific response. We did not find polygenic risk for epilepsy, neuropsychiatric disorders, and drug-resistance associated with drug response to specific ASMs or mechanistically related groups of ASMs. Significance: This study could not ascertain the predictive value of common genetic variants for ASM responder status. The identified suggestive loci will need replication in future studies of a larger scale.