Pharmacoresponse in Genetic Generalized Epilepsy: A Genome-Wide Association Study

Wolking, Stefan; Schulz, Herbert; Nies, Anne A.T.; McCormack, Mark; Schaeffeler, Elke; Auce, Pauls; Avberšek, Andreja; Becker, Felicitas; Klein, Karl Martin; Krenn, Martin; Møller, Rikke S.; Nikanorova, Marina; Weckhuysen, Sarah; Cavalleri, Gianpiero L.; Delanty, Norman; Depondt, Chantal; Johnson, Michael R.; Koeleman, Bobby P. C.; Kunz, W; Marson, Anthony G; Sander, Josemir W.; Sills, Graeme J.; Striano, Pasquale; Zara, Federico; Zimprich, Fritz; Weber, Yvonne; Krause, Roland; Sisodiya, Sanjay M.; Schwab, Matthias; Sander, Thomas; Lerche, Holger

doi:10.2217/pgs-2019-0179

Cited by 24 publications

(40 citation statements)

References 63 publications

(49 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…One study that examined common variants in candidate genes reported the ABCB1 drug transporter as well as in CACNA1H and CACNA1I, subunits of T‐type calcium channels, to be associated with response to ethosuximide and LTG . In previous studies, we aimed to identify common genetic variants via genome wide association studies (GWAS) based on single nucleotide polymorphism (SNP) chip data but failed to produce significant association signals for response to lacosamide, VPA, LTG, and LEV …”

Section: Introductionmentioning

confidence: 99%

Testing association of rare genetic variants with resistance to three common antiseizure medications

et al. 2020

Self Cite

View full text Add to dashboard Cite

Objective: Drug resistance is a major concern in the treatment of individuals with epilepsy. No genetic markers for resistance to individual antiseizure medication (ASM) have yet been identified. We aimed to identify the role of rare genetic variants in drug resistance for three common ASMs: levetiracetam (LEV), lamotrigine (LTG), and valproic acid (VPA). Methods: A cohort of 1622 individuals of European descent with epilepsy was deeply phenotyped and underwent whole exome sequencing (WES), comprising 575 taking LEV, 826 LTG, and 782 VPA. We performed gene-and gene set-based collapsing analyses comparing responders and nonresponders to the three drugs to determine the burden of different categories of rare genetic variants. Results: We observed a marginally significant enrichment of rare missense, truncating, and splice region variants in individuals who were resistant to VPA compared to VPA responders for genes involved in VPA pharmacokinetics. We also found a borderline significant enrichment of truncating and splice region variants in the synaptic vesicle glycoprotein (SV2) gene family in nonresponders compared to responders to LEV. We did not see any significant enrichment using a gene-based approach. Significance: In our pharmacogenetic study, we identified a slightly increased burden of damaging variants in gene groups related to drug kinetics or targeting in individuals presenting with drug resistance to VPA or LEV. Such variants could thus determine a genetic contribution to drug resistance.

show abstract

Section: Introductionmentioning

confidence: 99%

Testing association of rare genetic variants with resistance to three common antiseizure medications

et al. 2020

Self Cite

View full text Add to dashboard Cite

show abstract

“…WDR41 is a protein-coding gene and diseases associated with this gene include striatal degeneration, autosomal dominant 1, a rare autosomal-dominant movement disorder with some motor symptoms similar to PD, and frontotemporal dementia and/or amyotrophic lateral sclerosis 1, an autosomal dominant neurodegenerative disorder [ 21 ]. Importantly, several variants in WDR41 have been identified in previous GWAS having near genome-wide significant association signals for: Alzheimer’s disease (AD) ( p = 7 × 10 −7 ) [ 22 ]; caudate nucleus volume ( p = 2 × 10 −7 ), where caudate is a subcortical brain structure implicated in many common neurological and psychiatric disorders [ 23 ]; and epileptogenesis ( p = 5 × 10 −6 ) [ 24 ] in European populations. AD is also an age-related neurodegenerative condition caused by damaged brain cells and both PD and AD can involve common symptoms such as anxiety, depression, and sleep disturbances; some studies have noted shared risk variants across AD and PD [ 25 ].…”

Section: Discussionmentioning

confidence: 99%

Imputation and Reanalysis of ExomeChip Data Identifies Novel, Conditional and Joint Genetic Effects on Parkinson’s Disease Risk

Rodrigo

Nyholt

2021

Genes

View full text Add to dashboard Cite

Given that improved imputation software and high-coverage whole genome sequence (WGS)-based haplotype reference panels now enable inexpensive approximation of WGS genotype data, we hypothesised that WGS-based imputation and analysis of existing ExomeChip-based genome-wide association (GWA) data will identify novel intronic and intergenic single nucleotide polymorphism (SNP) effects associated with complex disease risk. In this study, we reanalysed a Parkinson’s disease (PD) dataset comprising 5540 cases and 5862 controls genotyped using the ExomeChip-based NeuroX array. After genotype imputation and extensive quality control, GWA analysis was performed using PLINK and a recently developed machine learning approach (GenEpi), to identify novel, conditional and joint genetic effects associated with PD. In addition to improved validation of previously reported loci, we identified five novel genome-wide significant loci associated with PD: three (rs137887044, rs78837976 and rs117672332) with 0.01 < MAF < 0.05, and two (rs187989831 and rs12100172) with MAF < 0.01. Conditional analysis within genome-wide significant loci revealed four loci (p < 1 × 10−5) with multiple independent risk variants, while GenEpi analysis identified SNP–SNP interactions in seven genes. In addition to identifying novel risk loci for PD, these results demonstrate that WGS-based imputation and analysis of existing exome genotype data can identify novel intronic and intergenic SNP effects associated with complex disease risk.

show abstract

“…[26][27][28]40 Our results support the association of rs2279020 with AEDsresistance, which contradicts the result in Chinese Han PWE, 40 but similar to Indian patients. 27 Moreover, as suggested that voltagedependent calcium channels (VDCCs) genes are one of the major effectors in pharmacogenetics of epilepsy, [41][42][43] A allele of CACNG5 rs740805 appear to associated with the drug resistance phenotype with a higher rate in resistant patients (323, 95% vs 225, 91% in the responsive group). This finding suggested the idea that other VDCCs genes may play a role in epilepsy treatment outcomes.…”

Section: Discussionmentioning

confidence: 99%

<p>Genetic Association of Epilepsy and Anti-Epileptic Drugs Treatment in Jordanian Patients</p>

AL-Eitan¹,

Al-Dalala²,

Elshammari³

et al. 2020

PGPM

View full text Add to dashboard Cite

The aim of this study was to investigate the possible effects of single-nucleotide polymorphisms (SNPs) within SLC1A1, SLC6A1, FAM131B, GPLD1, F2, GABRG2, GABRA1, and CACNG5 genes on response to anti-epileptic drugs (AEDs) and the genetic predisposition of epilepsy in Jordanian patients. Patients and Methods: A total of 299 healthy individuals and 296 pediatric patients from the Jordanian population were recruited. Blood samples are collected, and genotyping was performed using a custom platform array analysis. Results: The SLC1A1 rs10815018 and FAM131B rs4236482 polymorphisms found to be associated with epilepsy susceptibility. Moreover, SLC1A1 rs10815018 and GPLD1 rs1126617 polymorphisms were associated with generalized epilepsy (GE), while FAM131B rs4236482 is associated with the focal phenotype. Regarding the therapeutic response, the genetic polymorphisms of FAM131B rs4236482, GABRA1 rs2279020, and CACNG5 rs740805 are conferred poor response (resistance) to AEDs. There was no linkage of GLPD1 haplotypes to epilepsy, its subtypes, and treatment responsiveness. Conclusion: Our findings suggested that SLC1A1, FAM131B, and GPLD1 polymorphisms increasing the risk of generating epilepsy, while FAM131B, GABRA1, and CACNG5 variants may play a role in predicting drug response in patients with epilepsy (PWE).

show abstract

Pharmacoresponse in Genetic Generalized Epilepsy: A Genome-Wide Association Study

Cited by 24 publications

References 63 publications

Testing association of rare genetic variants with resistance to three common antiseizure medications

Testing association of rare genetic variants with resistance to three common antiseizure medications

Imputation and Reanalysis of ExomeChip Data Identifies Novel, Conditional and Joint Genetic Effects on Parkinson’s Disease Risk

<p>Genetic Association of Epilepsy and Anti-Epileptic Drugs Treatment in Jordanian Patients</p>

Contact Info

Product

Resources

About