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1

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Genetic variation in CFH predicts phenytoin-induced maculopapular exanthema in European-descent patients

McCormack, Mark ; Gui, Hongsheng ; Ingason, Andrés ; [et al.]

Ovid Technologies (Wolters Kluwer Health) ; 2018

In: Neurology Vol. 90, No. 4 ( 2018-01-23), p. e332-e341

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In: Neurology, Ovid Technologies (Wolters Kluwer Health), Vol. 90, No. 4 ( 2018-01-23), p. e332-e341

Abstract: To characterize, among European and Han Chinese populations, the genetic predictors of maculopapular exanthema (MPE), a cutaneous adverse drug reaction common to antiepileptic drugs. Methods We conducted a case-control genome-wide association study of autosomal genotypes, including Class I and II human leukocyte antigen (HLA) alleles, in 323 cases and 1,321 drug-tolerant controls from epilepsy cohorts of northern European and Han Chinese descent. Results from each cohort were meta-analyzed. Results We report an association between a rare variant in the complement factor H–related 4 ( CFHR4 ) gene and phenytoin-induced MPE in Europeans ( p = 4.5 × 10 –11 ; odds ratio [95% confidence interval] 7 [3.2–16] ). This variant is in complete linkage disequilibrium with a missense variant (N1050Y) in the complement factor H ( CFH ) gene. In addition, our results reinforce the association between HLA-A*31:01 and carbamazepine hypersensitivity. We did not identify significant genetic associations with MPE among Han Chinese patients. Conclusions The identification of genetic predictors of MPE in CFHR4 and CFH, members of the complement factor H–related protein family, suggest a new link between regulation of the complement system alternative pathway and phenytoin-induced hypersensitivity in European-ancestral patients.

Type of Medium: Online Resource

ISSN: 0028-3878 , 1526-632X

URL: Article

DOI: 10.1212/WNL.0000000000004853

RVK:

XA 10000

Language: English

Publisher: Ovid Technologies (Wolters Kluwer Health)

Publication Date: 2018

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Genome-wide mega-analysis identifies 16 loci and highlights diverse biological mechanisms in the common epilepsies

The International League Against Epilepsy Consortium on Complex Epilepsies ; Abou-Khalil, Bassel ; Auce, Pauls ; [et al.]

Springer Science and Business Media LLC ; 2018

In: Nature Communications Vol. 9, No. 1 ( 2018-12-10)

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In: Nature Communications, Springer Science and Business Media LLC, Vol. 9, No. 1 ( 2018-12-10)

Abstract: The epilepsies affect around 65 million people worldwide and have a substantial missing heritability component. We report a genome-wide mega-analysis involving 15,212 individuals with epilepsy and 29,677 controls, which reveals 16 genome-wide significant loci, of which 11 are novel. Using various prioritization criteria, we pinpoint the 21 most likely epilepsy genes at these loci, with the majority in genetic generalized epilepsies. These genes have diverse biological functions, including coding for ion-channel subunits, transcription factors and a vitamin-B6 metabolism enzyme. Converging evidence shows that the common variants associated with epilepsy play a role in epigenetic regulation of gene expression in the brain. The results show an enrichment for monogenic epilepsy genes as well as known targets of antiepileptic drugs. Using SNP-based heritability analyses we disentangle both the unique and overlapping genetic basis to seven different epilepsy subtypes. Together, these findings provide leads for epilepsy therapies based on underlying pathophysiology.

Type of Medium: Online Resource

ISSN: 2041-1723

URL: Article

DOI: 10.1038/s41467-018-07524-z

Language: English

Publisher: Springer Science and Business Media LLC

Publication Date: 2018

detail.hit.zdb_id: 2553671-0

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3

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Genome-wide identification and phenotypic characterization of seizure-associated copy number variations in 741,075 individuals

Montanucci, Ludovica ; Lewis-Smith, David ; Collins, Ryan L. ; [et al.]

Springer Science and Business Media LLC ; 2023

In: Nature Communications Vol. 14, No. 1 ( 2023-07-20)

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In: Nature Communications, Springer Science and Business Media LLC, Vol. 14, No. 1 ( 2023-07-20)

Abstract: Copy number variants (CNV) are established risk factors for neurodevelopmental disorders with seizures or epilepsy. With the hypothesis that seizure disorders share genetic risk factors, we pooled CNV data from 10,590 individuals with seizure disorders, 16,109 individuals with clinically validated epilepsy, and 492,324 population controls and identified 25 genome-wide significant loci, 22 of which are novel for seizure disorders, such as deletions at 1p36.33, 1q44, 2p21-p16.3, 3q29, 8p23.3-p23.2, 9p24.3, 10q26.3, 15q11.2, 15q12-q13.1, 16p12.2, 17q21.31, duplications at 2q13, 9q34.3, 16p13.3, 17q12, 19p13.3, 20q13.33, and reciprocal CNVs at 16p11.2, and 22q11.21. Using genetic data from additional 248,751 individuals with 23 neuropsychiatric phenotypes, we explored the pleiotropy of these 25 loci. Finally, in a subset of individuals with epilepsy and detailed clinical data available, we performed phenome-wide association analyses between individual CNVs and clinical annotations categorized through the Human Phenotype Ontology (HPO). For six CNVs, we identified 19 significant associations with specific HPO terms and generated, for all CNVs, phenotype signatures across 17 clinical categories relevant for epileptologists. This is the most comprehensive investigation of CNVs in epilepsy and related seizure disorders, with potential implications for clinical practice.

Type of Medium: Online Resource

ISSN: 2041-1723

URL: Article

DOI: 10.1038/s41467-023-39539-6

Language: English

Publisher: Springer Science and Business Media LLC

Publication Date: 2023

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4

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Ultra-Rare Genetic Variation in the Epilepsies: A Whole-Exome Sequencing Study of 17,606 Individuals

Feng, Yen-Chen Anne ; Howrigan, Daniel P. ; Abbott, Liam E. ; [et al.]

Elsevier BV ; 2019

In: The American Journal of Human Genetics Vol. 105, No. 2 ( 2019-08), p. 267-282

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In: The American Journal of Human Genetics, Elsevier BV, Vol. 105, No. 2 ( 2019-08), p. 267-282

Type of Medium: Online Resource

ISSN: 0002-9297

URL: Article

DOI: 10.1016/j.ajhg.2019.05.020

RVK:

XA 10000

Language: English

Publisher: Elsevier BV

Publication Date: 2019

detail.hit.zdb_id: 1473813-2

SSG: 12

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5

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Sub-genic intolerance, ClinVar, and the epilepsies: A whole-exome sequencing study of 29,165 individuals

Motelow, Joshua E. ; Povysil, Gundula ; Dhindsa, Ryan S. ; [et al.]

Elsevier BV ; 2021

In: The American Journal of Human Genetics Vol. 108, No. 10 ( 2021-10), p. 2024-

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In: The American Journal of Human Genetics, Elsevier BV, Vol. 108, No. 10 ( 2021-10), p. 2024-

Type of Medium: Online Resource

ISSN: 0002-9297

URL: Article

DOI: 10.1016/j.ajhg.2021.08.008

RVK:

XA 10000

Language: English

Publisher: Elsevier BV

Publication Date: 2021

detail.hit.zdb_id: 1473813-2

SSG: 12

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6

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Comparative effectiveness of antiepileptic drugs in patients with mesial temporal lobe epilepsy with hippocampal sclerosis

Androsova, Ganna ; Krause, Roland ; Borghei, Mojgansadat ; [et al.]

Wiley ; 2017

In: Epilepsia Vol. 58, No. 10 ( 2017-10), p. 1734-1741

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In: Epilepsia, Wiley, Vol. 58, No. 10 ( 2017-10), p. 1734-1741

Abstract: Mesial temporal lobe epilepsy with hippocampal sclerosis ( MTLE ‐ HS ) is a common epilepsy syndrome that is often poorly controlled by antiepileptic drug ( AED ) treatment. Comparative AED effectiveness studies in this condition are lacking. We report retention, efficacy, and tolerability in a cohort of patients with MTLE ‐ HS . Methods Clinical data were collected from a European database of patients with epilepsy. We estimated retention, 12‐month seizure freedom, and adverse drug reaction ( ADR ) rates for the 10 most commonly used AED s in patients with MTLE ‐ HS . Results Seven hundred sixty‐seven patients with a total of 3,249 AED trials were included. The highest 12‐month retention rates were observed with carbamazepine (85.9%), valproate (85%), and clobazam (79%). Twelve‐month seizure freedom rates varied from 1.2% for gabapentin and vigabatrin to 11% for carbamazepine. Response rates were highest for AED s that were prescribed as initial treatment and lowest for AED s that were used in a third or higher instance. ADR s were reported in 47.6% of patients, with the highest rates observed with oxcarbazepine (35.7%), topiramate (30.9%), and pregabalin (27.4%), and the lowest rates with clobazam (6.5%), gabapentin (8.9%), and lamotrigine (16.6%). The most commonly reported ADR s were lethargy and drowsiness, dizziness, vertigo and ataxia, and blurred vision and diplopia. Significance Our results did not demonstrate any clear advantage of newer versus older AED s. Our results provide useful insights into AED retention, efficacy, and ADR rates in patients with MTLE ‐ HS .

Type of Medium: Online Resource

ISSN: 0013-9580 , 1528-1167

URL: Issue

URL: Article

DOI: 10.1111/epi.2017.58.issue-10

DOI: 10.1111/epi.13871

RVK:

XA 10000

Language: English

Publisher: Wiley

Publication Date: 2017

detail.hit.zdb_id: 2002194-X

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7

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

Wolking, Stefan ; Moreau, Claudia ; Nies, Anne T. ; [et al.]

Wiley ; 2020

In: Epilepsia Vol. 61, No. 4 ( 2020-04), p. 657-666

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In: Epilepsia, Wiley, Vol. 61, No. 4 ( 2020-04), p. 657-666

Abstract: 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.

Type of Medium: Online Resource

ISSN: 0013-9580 , 1528-1167

URL: Issue

URL: Article

DOI: 10.1111/epi.v61.4

DOI: 10.1111/epi.16467

RVK:

XA 10000

Language: English

Publisher: Wiley

Publication Date: 2020

detail.hit.zdb_id: 2002194-X

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8

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GWAS meta-analysis of over 29,000 people with epilepsy identifies 26 risk loci and subtype-specific genetic architecture

International League Against Epilepsy Consortium on Complex Epilepsies ; Stevelink, Remi ; Campbell, Ciarán ; [et al.]

Springer Science and Business Media LLC ; 2023

In: Nature Genetics Vol. 55, No. 9 ( 2023-09), p. 1471-1482

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In: Nature Genetics, Springer Science and Business Media LLC, Vol. 55, No. 9 ( 2023-09), p. 1471-1482

Abstract: Epilepsy is a highly heritable disorder affecting over 50 million people worldwide, of which about one-third are resistant to current treatments. Here we report a multi-ancestry genome-wide association study including 29,944 cases, stratified into three broad categories and seven subtypes of epilepsy, and 52,538 controls. We identify 26 genome-wide significant loci, 19 of which are specific to genetic generalized epilepsy (GGE). We implicate 29 likely causal genes underlying these 26 loci. SNP-based heritability analyses show that common variants explain between 39.6% and 90% of genetic risk for GGE and its subtypes. Subtype analysis revealed markedly different genetic architectures between focal and generalized epilepsies. Gene-set analyses of GGE signals implicate synaptic processes in both excitatory and inhibitory neurons in the brain. Prioritized candidate genes overlap with monogenic epilepsy genes and with targets of current antiseizure medications. Finally, we leverage our results to identify alternate drugs with predicted efficacy if repurposed for epilepsy treatment.

Type of Medium: Online Resource

ISSN: 1061-4036 , 1546-1718

URL: Article

DOI: 10.1038/s41588-023-01485-w

RVK:

XA 10000

Language: English

Publisher: Springer Science and Business Media LLC

Publication Date: 2023

detail.hit.zdb_id: 1494946-5

SSG: 12

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9

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Comparative effectiveness of antiepileptic drugs in juvenile myoclonic epilepsy

Silvennoinen, Katri ; de Lange, Nikola ; Zagaglia, Sara ; [et al.]

Wiley ; 2019

In: Epilepsia Open Vol. 4, No. 3 ( 2019-09), p. 420-430

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In: Epilepsia Open, Wiley, Vol. 4, No. 3 ( 2019-09), p. 420-430

Abstract: To study the effectiveness and tolerability of antiepileptic drugs (AEDs) commonly used in juvenile myoclonic epilepsy (JME). Methods People with JME were identified from a large database of individuals with epilepsy, which includes detailed retrospective information on AED use. We assessed secular changes in AED use and calculated rates of response (12‐month seizure freedom) and adverse drug reactions (ADRs) for the five most common AEDs. Retention was modeled with a Cox proportional hazards model. We compared valproate use between males and females. Results We included 305 people with 688 AED trials of valproate, lamotrigine, levetiracetam, carbamazepine, and topiramate. Valproate and carbamazepine were most often prescribed as the first AED. The response rate to valproate was highest among the five AEDs (42.7%), and significantly higher than response rates for lamotrigine, carbamazepine, and topiramate; the difference to the response rate to levetiracetam (37.1%) was not significant. The rates of ADRs were highest for topiramate (45.5%) and valproate (37.5%). Commonest ADRs included weight change, lethargy, and tremor. In the Cox proportional hazards model, later start year (1.10 [1.08‐1.13], P 〈 0.001) and female sex (1.41 [1.07‐1.85], P = 0.02) were associated with shorter trial duration. Valproate was associated with the longest treatment duration; trials with carbamazepine and topiramate were significantly shorter (HR [CI]: 3.29 [2.15‐5.02] , P 〈 0.001 and 1.93 [1.31‐2.86], P 〈 0.001). The relative frequency of valproate trials shows a decreasing trend since 2003 while there is an increasing trend for levetiracetam. Fewer females than males received valproate (76.2% vs 92.6%, P = 0.001). Significance In people with JME, valproate is an effective AED; levetiracetam emerged as an alternative. Valproate is now contraindicated in women of childbearing potential without special precautions. With appropriate selection and safeguards in place, valproate should remain available as a therapy, including as an alternative for women of childbearing potential whose seizures are resistant to other treatments.

Type of Medium: Online Resource

ISSN: 2470-9239 , 2470-9239

URL: Issue

URL: Article

DOI: 10.1002/epi4.v4.3

DOI: 10.1002/epi4.12349

Language: English

Publisher: Wiley

Publication Date: 2019

detail.hit.zdb_id: 2863427-5

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10

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Sub-genic intolerance, ClinVar, and the epilepsies: A whole-exome sequencing study of 29,165 individuals

Motelow, Joshua E. ; Povysil, Gundula ; Dhindsa, Ryan S. ; [et al.]

Elsevier BV ; 2021

In: The American Journal of Human Genetics Vol. 108, No. 6 ( 2021-06), p. 965-982

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In: The American Journal of Human Genetics, Elsevier BV, Vol. 108, No. 6 ( 2021-06), p. 965-982

Type of Medium: Online Resource

ISSN: 0002-9297

URL: Article

DOI: 10.1016/j.ajhg.2021.04.009

RVK:

XA 10000

Language: English

Publisher: Elsevier BV

Publication Date: 2021

detail.hit.zdb_id: 1473813-2

SSG: 12

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