AUTHOR=Wolking Stefan , Campbell Ciarán , Stapleton Caragh , McCormack Mark , Delanty Norman , Depondt Chantal , Johnson Michael R. , Koeleman Bobby P. C. , Krause Roland , Kunz Wolfram S. , Marson Anthony G. , Sander Josemir W. , Sills Graeme J. , Striano Pasquale , Zara Federico , Sisodiya Sanjay M. , Cavalleri Gianpiero L. , Lerche Holger ,  EpiPGX Consortium 

TITLE=Role of Common Genetic Variants for Drug-Resistance to Specific Anti-Seizure Medications

JOURNAL=Frontiers in Pharmacology

VOLUME=12

YEAR=2021

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2021.688386

DOI=10.3389/fphar.2021.688386

ISSN=1663-9812

ABSTRACT=<p><bold>Objective:</bold> 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.</p><p><bold>Methods:</bold> 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.</p><p><bold>Results:</bold> 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.</p><p><bold>Significance:</bold> 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.</p>