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