Assessing the role of rare genetic variants in drug-resistant, non-lesional focal epilepsy

Wolking, S. et al. (2021) Assessing the role of rare genetic variants in drug-resistant, non-lesional focal epilepsy. Annals of Clinical and Translational Neurology, 8(7), pp. 1376-1387. (doi: 10.1002/acn3.51374) (PMID:34018700)

Abstract

Objective: Resistance to antiseizure medications (ASMs) is one of the major concerns in the treatment of epilepsy. Despite the increasing number of ASMs available, the proportion of individuals with drug-resistant epilepsy remains unchanged. In this study, we aimed to investigate the role of rare genetic variants in ASM resistance. Methods: We performed exome sequencing of 1,128 individuals with non-familial non-acquired focal epilepsy (NAFE) (762 non-responders, 366 responders) and were provided with 1,734 healthy controls. We undertook replication in a cohort of 350 individuals with NAFE (165 non-responders, 185 responders). We performed gene-based and gene-set-based kernel association tests to investigate potential enrichment of rare variants in relation to drug response status and to risk for NAFE. Results: We found no gene or gene set that reached genome-wide significance. Yet, we identified several prospective candidate genes – among them DEPDC5, which showed a potential association with resistance to ASMs. We found some evidence for an enrichment of truncating variants in dominant familial NAFE genes in our cohort of non-familial NAFE and in association with drug-resistant NAFE. Interpretation: Our study identifies potential candidate genes for ASM resistance. Our results corroborate the role of rare variants for non-familial NAFE and imply their involvement in drug-resistant epilepsy. Future large-scale genetic research studies are needed to substantiate these findings.

• Item Type: Articles
• Additional Information: CENet was funded by joint funding from Genome Canada and Genome Quebec. The EpiPGX Consortium was funded by FP7 grant 279062 “EpiPGX” from the European Commission. SW received funding from the German Research Foundation (DFG) (WO 2385/1-1). The computational analysis was performed on the Compute Canada cluster Beluga. The samples for the replication cohort were kindly provided by the Epi4K-consortium.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Sills, Dr Graeme
• Authors: Wolking, S., Moreau, C., McCormack, M., Krause, R., Krenn, M., EpiPGx Consortium, , Berkovic, S., Cavalleri, G. L., Delanty, N., Depondt, C., Johnson, M. R., Koeleman, B. P.C., Kunz, W. S., Lerche, H., Marson, A. G., O’Brien, T. J., Petrovski, S., Sander, J. W., Sills, G. J., Striano, P., Zara, F., Zimprich, F., Sisodiya, S. M., Girard, S. L., and Cossette, P.
• College/School: College of Medical Veterinary and Life Sciences > School of Life Sciences
• Journal Name: Annals of Clinical and Translational Neurology
• Publisher: Wiley
• ISSN: 2328-9503
• ISSN (Online): 2328-9503
• Published Online: 21 May 2021
• Copyright Holders: Copyright © 2021 The Authors
• First Published: First published in Annals of Clinical and Translational Neurology 8(7): 1376-1387
• Publisher Policy: Reproduced under a Creative Commons License