Published 2021
| Version v1
Publication
Assessing the role of rare genetic variants in drug-resistant, non-lesional focal epilepsy
Creators
- Wolking S.
- Moreau C.
- McCormack M.
- Krause R.
- Krenn M.
- 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.
- Cossette P.
- Avbersek A.
- Leu C.
- Heggeli K.
- Demurtas R.
- Willis J.
- Speed D.
- Sargsyan N.
- Chinthapalli K.
- Borghei M.
- Coppola A.
- Gambardella A.
- Becker F.
- Rau S.
- Hengsbach C.
- Weber Y. G.
- Berghuis B.
- Campbell E.
- Gudmundsson L. J.
- Ingason A.
- Stefansson K.
- Schneider R.
- Balling R.
- Auce P.
- Francis B.
- Jorgensen A.
- Morris A.
- Langley S.
- Srivastava P.
- Brodie M.
- Todaro M.
- Hutton J.
- Muhle H.
- Klein K. M.
- Moller R. S.
- Nikanorova M.
- Weckhuysen S.
- Rener-Primec Z.
- Craig J.
- Stefansson H.
Contributors
Others:
- Wolking, S.
- Moreau, C.
- Mccormack, M.
- Krause, R.
- Krenn, M.
- 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.
- Cossette, P.
- Avbersek, A.
- Leu, C.
- Heggeli, K.
- Demurtas, R.
- Willis, J.
- Speed, D.
- Sargsyan, N.
- Chinthapalli, K.
- Borghei, M.
- Coppola, A.
- Gambardella, A.
- Becker, F.
- Rau, S.
- Hengsbach, C.
- Weber, Y. G.
- Berghuis, B.
- Campbell, E.
- Gudmundsson, L. J.
- Ingason, A.
- Stefansson, K.
- Schneider, R.
- Balling, R.
- Auce, P.
- Francis, B.
- Jorgensen, A.
- Morris, A.
- Langley, S.
- Srivastava, P.
- Brodie, M.
- Todaro, M.
- Hutton, J.
- Muhle, H.
- Klein, K. M.
- Moller, R. S.
- Nikanorova, M.
- Weckhuysen, S.
- Rener-Primec, Z.
- Craig, J.
- Stefansson, H.
Description
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.
Additional details
Identifiers
- URL
- http://hdl.handle.net/11567/1083870
- URN
- urn:oai:iris.unige.it:11567/1083870
Origin repository
- Origin repository
- UNIGE