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Exome sequencing of 20,979 individuals with epilepsy reveals shared and distinct ultra-rare genetic risk across disorder subtypes

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dc.contributor.authorTÜRKDOĞAN, DİLŞAD
dc.contributor.authorsBerkovic S. F., Neale B. M., Zsurka G., Zizovic M., Zimprich F., Zara F., Zahnert F., Zagaglia S., YÜCESAN E., Yolken R., et al.
dc.date.accessioned2024-10-22T16:22:04Z
dc.date.available2024-10-22T16:22:04Z
dc.date.issued2024-10-01
dc.description.abstractIdentifying genetic risk factors for highly heterogeneous disorders such as epilepsy remains challenging. Here we present, to our knowledge, the largest whole-exome sequencing study of epilepsy to date, with more than 54,000 human exomes, comprising 20,979 deeply phenotyped patients from multiple genetic ancestry groups with diverse epilepsy subtypes and 33,444 controls, to investigate rare variants that confer disease risk. These analyses implicate seven individual genes, three gene sets and four copy number variants at exome-wide significance. Genes encoding ion channels show strong association with multiple epilepsy subtypes, including epileptic encephalopathies and generalized and focal epilepsies, whereas most other gene discoveries are subtype specific, highlighting distinct genetic contributions to different epilepsies. Combining results from rare single-nucleotide/short insertion and deletion variants, copy number variants and common variants, we offer an expanded view of the genetic architecture of epilepsy, with growing evidence of convergence among different genetic risk loci on the same genes. Top candidate genes are enriched for roles in synaptic transmission and neuronal excitability, particularly postnatally and in the neocortex. We also identify shared rare variant risk between epilepsy and other neurodevelopmental disorders. Our data can be accessed via an interactive browser, hopefully facilitating diagnostic efforts and accelerating the development of follow-up studies.
dc.identifier.citationBerkovic S. F., Neale B. M., Zsurka G., Zizovic M., Zimprich F., Zara F., Zahnert F., Zagaglia S., YÜCESAN E., Yolken R., et al., "Exome sequencing of 20,979 individuals with epilepsy reveals shared and distinct ultra-rare genetic risk across disorder subtypes", Nature Neuroscience, cilt.27, sa.10, ss.1864-1879, 2024
dc.identifier.doi10.1038/s41593-024-01747-8
dc.identifier.endpage1879
dc.identifier.issn1097-6256
dc.identifier.issue10
dc.identifier.startpage1864
dc.identifier.urihttps://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85205532641&origin=inward
dc.identifier.urihttps://hdl.handle.net/11424/298114
dc.identifier.volume27
dc.language.isoeng
dc.relation.ispartofNature Neuroscience
dc.rightsinfo:eu-repo/semantics/openAccess
dc.subjectYaşam Bilimleri
dc.subjectTemel Bilimler
dc.subjectLife Sciences
dc.subjectNatural Sciences
dc.subjectYaşam Bilimleri (Life)
dc.subjectSinirbilim Ve Davranış
dc.subjectSinir Bilimi
dc.subjectLife Sciences (Life)
dc.subjectNeuroscience & Behavior
dc.subjectNeurosciences
dc.subjectGenel Sinirbilim
dc.subjectGeneral Neuroscience
dc.titleExome sequencing of 20,979 individuals with epilepsy reveals shared and distinct ultra-rare genetic risk across disorder subtypes
dc.typearticle
dspace.entity.typePublication
local.avesis.id911d6681-44bb-4e7e-aabc-526de8335bac
local.indexed.atPUBMED
local.indexed.atSCOPUS
relation.isAuthorOfPublication0a1599c4-48ff-4aa9-b689-3927c986a650
relation.isAuthorOfPublication.latestForDiscovery0a1599c4-48ff-4aa9-b689-3927c986a650

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