Role of common genetic variants for drug-resistance to specific anti-seizure medications

Wolking, S. et al. (2021) Role of common genetic variants for drug-resistance to specific anti-seizure medications. Frontiers in Pharmacology, 12, 688386. (doi: 10.3389/fphar.2021.688386) (PMID:34177598) (PMCID:PMC8220970)

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.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Sills, Dr Graeme
• Authors: Wolking, S., Campbell, C., Stapleton, C., McCormack, M., Delanty, N., Depondt, C., Johnson, M. R., Koeleman, B. P. C., Krause, R., Kunz, W. S., Marson, A. G., Sander, J. W., Sills, G. J., Striano, P., Zara, F., Sisodiya, S. M., Cavalleri, G. L., and Lerche, H.
• College/School: College of Medical Veterinary and Life Sciences > School of Life Sciences
• Journal Name: Frontiers in Pharmacology
• Publisher: Frontiers Media
• ISSN: 1663-9812
• ISSN (Online): 1663-9812
• Copyright Holders: Copyright © 2021 Wolking, Campbell, Stapleton, McCormack, Delanty, Depondt, Johnson, Koeleman, Krause, Kunz, Marson, Sander, Sills, Striano, Zara, Sisodiya, Cavalleri, Lerche and EpiPGX Consortium
• First Published: First published in Frontiers in Pharmacology 12: 688386
• Publisher Policy: Reproduced under a Creative Commons License