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

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posted on 27.07.2021, 15:20 authored by Stefan Wolking, Ciaran CampbellCiaran Campbell, Caragh Stapleton, Mark McCormack, Norman Delanty, Chantal Depondt, Michael R Johnson, Bobby PC Koeleman, Roland Krause, Wolfram S Kunz, Anthony G Marson, Josemir W Sander, Graeme J Sills, Pasquale Striano, Federico Zara, Sanjay M Sisodiya, Gianpiero CavalleriGianpiero Cavalleri, Holger Lerche, EpiPGX Consortium

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.

Funding

FP7 grant 279062 “EpiPGX” from the European Commission

German Research Foundation (DFG) (WO 2385/1-1)

History

Comments

The original article is available at https://www.frontiersin.org

Published Citation

Wolking S, et al. Role of common genetic variants for drug-resistance to specific anti-seizure medications. Front Pharmacol. 2021;12:688386.

Publication Date

9 June 2021

PubMed ID

34177598

Department/Unit

  • Beaumont Hospital
  • FutureNeuro Centre
  • School of Pharmacy and Biomolecular Sciences

Research Area

  • Neurological and Psychiatric Disorders

Publisher

Frontiers Media SA

Version

  • Published Version (Version of Record)