Universität zu Köln

Campbell, Ciaran ORCID: 0000-0001-8267-5252, Leu, Costin, Feng, Yen-Chen Anne, Wolking, Stefan ORCID: 0000-0002-1460-6623, Moreau, Claudia ORCID: 0000-0002-1480-3045, Ellis, Colin, Ganesan, Shiva, Martins, Helena, Oliver, Karen, Boothman, Isabelle ORCID: 0000-0002-3056-9121, Benson, Katherine, Molloy, Anne, Brody, Lawrence, Michaud, Jacques L., Hamdan, Fadi F., Minassian, Berge A., Lerche, Holger, Scheffer, Ingrid E., Sisodiya, Sanjay, Girard, Simon, Cosette, Patrick, Delanty, Norman, Lal, Dennis and Cavalleri, Gianpiero L. (2022). The role of common genetic variation in presumed monogenic epilepsies. EBioMedicine, 81. AMSTERDAM: ELSEVIER. ISSN 2352-3964

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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.Copyright (c) 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/)

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Campbell, Ciaran UNSPECIFIED orcid.org/0000-0001-8267-5252 UNSPECIFIED Leu, Costin UNSPECIFIED UNSPECIFIED UNSPECIFIED Feng, Yen-Chen Anne UNSPECIFIED UNSPECIFIED UNSPECIFIED Wolking, Stefan UNSPECIFIED orcid.org/0000-0002-1460-6623 UNSPECIFIED Moreau, Claudia UNSPECIFIED orcid.org/0000-0002-1480-3045 UNSPECIFIED Ellis, Colin UNSPECIFIED UNSPECIFIED UNSPECIFIED Ganesan, Shiva UNSPECIFIED UNSPECIFIED UNSPECIFIED Martins, Helena UNSPECIFIED UNSPECIFIED UNSPECIFIED Oliver, Karen UNSPECIFIED UNSPECIFIED UNSPECIFIED Boothman, Isabelle UNSPECIFIED orcid.org/0000-0002-3056-9121 UNSPECIFIED Benson, Katherine UNSPECIFIED UNSPECIFIED UNSPECIFIED Molloy, Anne UNSPECIFIED UNSPECIFIED UNSPECIFIED Brody, Lawrence UNSPECIFIED UNSPECIFIED UNSPECIFIED Michaud, Jacques L. UNSPECIFIED UNSPECIFIED UNSPECIFIED Hamdan, Fadi F. UNSPECIFIED UNSPECIFIED UNSPECIFIED Minassian, Berge A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Lerche, Holger UNSPECIFIED UNSPECIFIED UNSPECIFIED Scheffer, Ingrid E. UNSPECIFIED UNSPECIFIED UNSPECIFIED Sisodiya, Sanjay UNSPECIFIED UNSPECIFIED UNSPECIFIED Girard, Simon UNSPECIFIED UNSPECIFIED UNSPECIFIED Cosette, Patrick UNSPECIFIED UNSPECIFIED UNSPECIFIED Delanty, Norman UNSPECIFIED UNSPECIFIED UNSPECIFIED Lal, Dennis UNSPECIFIED UNSPECIFIED UNSPECIFIED Cavalleri, Gianpiero L. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-697417
DOI:	10.1016/j.ebiom.2022.104098
Journal or Publication Title:	EBioMedicine
Volume:	81
Date:	2022
Publisher:	ELSEVIER
Place of Publication:	AMSTERDAM
ISSN:	2352-3964
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language JOINT CONSENSUS RECOMMENDATION; DE-NOVO MUTATIONS; EPILEPTIC ENCEPHALOPATHIES; MEDICAL GENETICS; AMERICAN-COLLEGE; EXOME; STANDARDS; VARIANTS; RESOURCE; GENOMICS Multiple languages Medicine, General & Internal; Medicine, Research & Experimental Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/69741