eprintid: 10151331
rev_number: 7
eprint_status: archive
userid: 699
dir: disk0/10/15/13/31
datestamp: 2022-07-07 16:56:58
lastmod: 2022-07-07 16:56:58
status_changed: 2022-07-07 16:56:58
type: article
metadata_visibility: show
sword_depositor: 699
creators_name: Campbell, Ciarán
creators_name: Leu, Costin
creators_name: Feng, Yen-Chen Anne
creators_name: Wolking, Stefan
creators_name: Moreau, Claudia
creators_name: Ellis, Colin
creators_name: Ganesan, Shiva
creators_name: Martins, Helena
creators_name: Oliver, Karen
creators_name: Boothman, Isabelle
creators_name: Benson, Katherine
creators_name: Molloy, Anne
creators_name: Brody, Lawrence
creators_name: Epi4K Collaborative, 
creators_name: Genomics England Research Consortium, 
creators_name: Michaud, Jacques L
creators_name: Hamdan, Fadi F
creators_name: Minassian, Berge A
creators_name: Lerche, Holger
creators_name: Scheffer, Ingrid E
creators_name: Sisodiya, Sanjay
creators_name: Girard, Simon
creators_name: Cosette, Patrick
creators_name: Delanty, Norman
creators_name: Lal, Dennis
creators_name: Cavalleri, Gianpiero L
creators_name: Epi25 Collaborative, 
title: The role of common genetic variation in presumed monogenic epilepsies
ispublished: pub
divisions: C07
divisions: F81
divisions: B02
divisions: UCL
divisions: D07
keywords: DEEs, Epilepsy, Genetic diagnostics, PRS
note: © 2022 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY license
(http://creativecommons.org/licenses/by/4.0/)
abstract: BACKGROUND: The developmental and epileptic encephalopathies (DEEs) are the most severe group of epilepsies which co-present with developmental delay and intellectual disability (ID). DEEs usually occur in people without a family history of epilepsy and have emerged as primarily monogenic, with damaging rare mutations found in 50% of patients. Little is known about the genetic architecture of patients with DEEs in whom no pathogenic variant is identified. Polygenic risk scoring (PRS) is a method that measures a person's common genetic burden for a trait or condition. Here, we used PRS to test whether genetic burden for epilepsy is relevant in individuals with DEEs, and other forms of epilepsy with ID. METHODS: Genetic data on 2,759 cases with DEEs, or epilepsy with ID presumed to have a monogenic basis, and 447,760 population-matched controls were analysed. We compared PRS for 'all epilepsy', 'focal epilepsy', and 'genetic generalised epilepsy' (GGE) between cases and controls. We performed pairwise comparisons between cases stratified for identifiable rare deleterious genetic variants and controls. FINDINGS: Cases of presumed monogenic severe epilepsy had an increased PRS for 'all epilepsy' (p<0.0001), 'focal epilepsy' (p<0.0001), and 'GGE' (p=0.0002) relative to controls, which explain between 0.08% and 3.3% of phenotypic variance. PRS was increased in cases both with and without an identified deleterious variant of major effect, and there was no significant difference in PRS between the two groups. INTERPRETATION: We provide evidence that common genetic variation contributes to the aetiology of DEEs and other forms of epilepsy with ID, even when there is a known pathogenic variant of major effect. These results provide insight into the genetic underpinnings of the severe epilepsies and warrant a shift in our understanding of the aetiology of the DEEs as complex, rather than monogenic, disorders. FUNDING: Science foundation Ireland, Human Genome Research Institute; National Heart, Lung, and Blood Institute; German Research Foundation.
date: 2022-07
date_type: published
publisher: Elsevier BV
official_url: https://doi.org/10.1016/j.ebiom.2022.104098
oa_status: green
full_text_type: pub
language: eng
primo: open
primo_central: open_green
verified: verified_manual
elements_id: 1961778
doi: 10.1016/j.ebiom.2022.104098
medium: Print-Electronic
pii: S2352-3964(22)00279-1
lyricists_name: Sisodiya, Sanjay
lyricists_id: SMSIS90
actors_name: Flynn, Bernadette
actors_id: BFFLY94
actors_role: owner
full_text_status: public
publication: EBioMedicine
volume: 81
article_number: 104098
event_location: Netherlands
citation:        Campbell, Ciarán;    Leu, Costin;    Feng, Yen-Chen Anne;    Wolking, Stefan;    Moreau, Claudia;    Ellis, Colin;    Ganesan, Shiva;                                                                                 ... Epi25 Collaborative; + view all <#>        Campbell, Ciarán;  Leu, Costin;  Feng, Yen-Chen Anne;  Wolking, Stefan;  Moreau, Claudia;  Ellis, Colin;  Ganesan, Shiva;  Martins, Helena;  Oliver, Karen;  Boothman, Isabelle;  Benson, Katherine;  Molloy, Anne;  Brody, Lawrence;  Epi4K Collaborative;  Genomics England Research Consortium;  Michaud, Jacques L;  Hamdan, Fadi F;  Minassian, Berge A;  Lerche, Holger;  Scheffer, Ingrid E;  Sisodiya, Sanjay;  Girard, Simon;  Cosette, Patrick;  Delanty, Norman;  Lal, Dennis;  Cavalleri, Gianpiero L;  Epi25 Collaborative;   - view fewer <#>    (2022)    The role of common genetic variation in presumed monogenic epilepsies.                   EBioMedicine , 81     , Article 104098.  10.1016/j.ebiom.2022.104098 <https://doi.org/10.1016/j.ebiom.2022.104098>.       Green open access   
 
document_url: https://discovery.ucl.ac.uk/id/eprint/10151331/1/1-s2.0-S2352396422002791-main.pdf