Common risk variants for epilepsy are enriched in families previously targeted for rare monogenic variant discovery

Oliver, Karen; Ellis, Colin A; Scheffer, Ingrid E.; Ganesan, Shiva; Leu, Costin; Sadleir, Lynette G.; Heinzen, Erin L.; Mefford, Heather C; Bass, Andrew J.; Curtis, Sarah W.; Harris, Rebekah V.; Whiteman, David C.; Helbig, Ingo; Ottman, Ruth; Epstein, Michael P.; Bahlo, Melanie; Berkovic, Samuel F.

doi:10.1016/j.ebiom.2022.104079

Cited by 16 publications

(16 citation statements)

References 41 publications

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“…Our recent study on PRS in families with all types of epilepsy demonstrated a role for common epilepsy risk variants, but when stratified for focal versus generalized epilepsy type, such a role appeared limited to familial genetic generalized epilepsies 22 . In that study, within heterogeneous focal syndromes, we did not demonstrate an elevated focal epilepsy polygenic risk burden in cases with a family history of epilepsy (n = 601), nor in those with sporadic focal epilepsy (n = 675), compared to population controls 22 …”

Section: Discussionmentioning

confidence: 92%

“…Using GWAS data to calculate polygenic risk scores (PRS)–a weighted sum of the number of common epilepsy risk alleles an individual carries–has proven less powerful for focal epilepsy compared to genetic generalized epilepsy 22,23 . Furthermore, in a cohort of individuals with focal epilepsy and a family history of epilepsy, no significant enrichment of PRS for focal epilepsy (generated using data from the 2018 “ILAE 2” GWAS) was observed compared to population controls 22 . Given the heterogeneous nature of the focal epilepsies, genetic analysis of a more homogeneous focal epilepsy subcohort, such as FMTLE, may be more informative.…”

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confidence: 99%

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Familial Mesial Temporal Lobe Epilepsy: Clinical Spectrum and Genetic Evidence for a Polygenic Architecture

Harris,

Oliver,

Perucca

et al. 2023

Annals of Neurology

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ObjectiveFamilial mesial temporal lobe epilepsy (FMTLE) is an important focal epilepsy syndrome; its molecular genetic basis is unknown. Clinical descriptions of FMTLE vary between a mild syndrome with prominent déjà vu to a more severe phenotype with febrile seizures and hippocampal sclerosis. We aimed to refine the phenotype of FMTLE by analyzing a large cohort of patients and asked whether common risk variants for focal epilepsy and/or febrile seizures, measured by polygenic risk scores (PRS), are enriched in individuals with FMTLE.MethodsWe studied 134 families with ≥ 2 first or second‐degree relatives with temporal lobe epilepsy, with clear mesial ictal semiology required in at least one individual. PRS were calculated for 227 FMTLE cases, 124 unaffected relatives, and 16,077 population controls.ResultsThe age of patients with FMTLE onset ranged from 2.5 to 70 years (median = 18, interquartile range = 13–28 years). The most common focal seizure symptom was déjà vu (62% of cases), followed by epigastric rising sensation (34%), and fear or anxiety (22%). The clinical spectrum included rare cases with drug‐resistance and/or hippocampal sclerosis. FMTLE cases had a higher mean focal epilepsy PRS than population controls (odds ratio = 1.24, 95% confidence interval = 1.06, 1.46, p = 0.007); in contrast, no enrichment for the febrile seizure PRS was observed.InterpretationFMTLE is a generally mild drug‐responsive syndrome with déjà vu being the commonest symptom. In contrast to dominant monogenic focal epilepsy syndromes, our molecular data support a polygenic basis for FMTLE. Furthermore, the PRS data suggest that sub‐genome‐wide significant focal epilepsy genome‐wide association study single nucleotide polymorphisms are important risk variants for FMTLE. ANN NEUROL 2023

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Section: Discussionmentioning

confidence: 92%

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confidence: 99%

Familial Mesial Temporal Lobe Epilepsy: Clinical Spectrum and Genetic Evidence for a Polygenic Architecture

Harris,

Oliver,

Perucca

et al. 2023

Annals of Neurology

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“…Over 7000 cases and 83 000 controls were analysed to attain these results, reflecting the massive numbers of research participants that will be required to further define and investigate polygenic risk. Complex inheritance of multiple, common variants in key genes have also been analysed using data from international consortia for sporadically affected individuals, as well as people with familial epilepsy and their unaffected relatives [29]. This analysis was able to demonstrate that individuals with familial epilepsies [odds ratio (OR) 1.20] and sporadic epilepsies (OR 1.09) had an elevated polygenic risk compared with controls.…”

Section: Polygenic and Other Genetic Mechanismsmentioning

confidence: 99%

The current landscape of epilepsy genetics: where are we, and where are we going?

Ruggiero

Xian

Helbig

2023

Current Opinion in Neurology

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Purpose of reviewIn this review, we aim to analyse the progress in understanding the genetic basis of the epilepsies, as well as ongoing efforts to define the increasingly diverse and novel presentations, phenotypes and divergences from the expected that have continually characterized the field.Recent findingsA genetic workup is now considered to be standard of care for individuals with an unexplained epilepsy, due to mounting evidence that genetic diagnoses significantly influence treatment choices, prognostication, community support, and increasingly, access to clinical trials. As more individuals with epilepsy are tested, novel presentations of known epilepsy genes are being discovered, and more individuals with self-limited epilepsy are able to attain genetic diagnoses. In addition, new genes causative of epilepsy are being uncovered through both traditional and novel methods, including large international data-sharing collaborations and massive sequencing efforts as well as computational methods and analyses driven by the Human Phenotype Ontology (HPO).SummaryNew approaches to gene discovery and characterization are advancing rapidly our understanding of the genetic and phenotypic architecture of the epilepsies. This review highlights relevant and groundbreaking studies published recently that have pushed forward the field of epilepsy genetics.

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“…Indeed, salient phenotypic variations are not uncommon among individuals carrying identical variants ( Helbig and Tayoun, 2016 ). Recent studies underline that common genetic variants are enriched in persons and families investigated for rare disease-causing variants, hinting at a broad array of influences, that shape a phenotype observed in a patient ( Campbell et al, 2022 ; Oliver et al, 2022 ). Polygenic mechanisms that influence such epileptic phenotypes might be difficult to study in Drosophila , as they are large in numbers with low effect-sizes.…”

Section: Drosophila Genetics and Tools To Investigate Seizur...mentioning

confidence: 99%

Drosophila melanogaster as a versatile model organism to study genetic epilepsies: An overview

Fischer

Karge²,

Weber³

et al. 2023

Front. Mol. Neurosci.

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Epilepsy is one of the most prevalent neurological disorders, affecting more than 45 million people worldwide. Recent advances in genetic techniques, such as next-generation sequencing, have driven genetic discovery and increased our understanding of the molecular and cellular mechanisms behind many epilepsy syndromes. These insights prompt the development of personalized therapies tailored to the genetic characteristics of an individual patient. However, the surging number of novel genetic variants renders the interpretation of pathogenetic consequences and of potential therapeutic implications ever more challenging. Model organisms can help explore these aspects in vivo. In the last decades, rodent models have significantly contributed to our understanding of genetic epilepsies but their establishment is laborious, expensive, and time-consuming. Additional model organisms to investigate disease variants on a large scale would be desirable. The fruit fly Drosophila melanogaster has been used as a model organism in epilepsy research since the discovery of “bang-sensitive” mutants more than half a century ago. These flies respond to mechanical stimulation, such as a brief vortex, with stereotypic seizures and paralysis. Furthermore, the identification of seizure-suppressor mutations allows to pinpoint novel therapeutic targets. Gene editing techniques, such as CRISPR/Cas9, are a convenient way to generate flies carrying disease-associated variants. These flies can be screened for phenotypic and behavioral abnormalities, shifting of seizure thresholds, and response to anti-seizure medications and other substances. Moreover, modification of neuronal activity and seizure induction can be achieved using optogenetic tools. In combination with calcium and fluorescent imaging, functional alterations caused by mutations in epilepsy genes can be traced. Here, we review Drosophila as a versatile model organism to study genetic epilepsies, especially as 81% of human epilepsy genes have an orthologous gene in Drosophila. Furthermore, we discuss newly established analysis techniques that might be used to further unravel the pathophysiological aspects of genetic epilepsies.

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Common risk variants for epilepsy are enriched in families previously targeted for rare monogenic variant discovery

Cited by 16 publications

References 41 publications

Familial Mesial Temporal Lobe Epilepsy: Clinical Spectrum and Genetic Evidence for a Polygenic Architecture

Familial Mesial Temporal Lobe Epilepsy: Clinical Spectrum and Genetic Evidence for a Polygenic Architecture

The current landscape of epilepsy genetics: where are we, and where are we going?

Drosophila melanogaster as a versatile model organism to study genetic epilepsies: An overview

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