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. 2022 Jul:81:104098.
doi: 10.1016/j.ebiom.2022.104098. Epub 2022 Jun 6.

The role of common genetic variation in presumed monogenic epilepsies

Ciarán Campbell  1 , Costin Leu  2 , Yen-Chen Anne Feng  3 , Stefan Wolking  4 , Claudia Moreau  5 , Colin Ellis  6 , Shiva Ganesan  7 , Helena Martins  8 , Karen Oliver  9 , Isabelle Boothman  1 , Katherine Benson  1 , Anne Molloy  10 , Lawrence Brody  11 ; Epi4K Collaborative; Genomics England Research Consortium; Jacques L Michaud  12 , Fadi F Hamdan  12 , Berge A Minassian  13 , Holger Lerche  14 , Ingrid E Scheffer  15 , Sanjay Sisodiya  8 , Simon Girard  5 , Patrick Cosette  16 , Norman Delanty  17 , Dennis Lal  18 , Gianpiero L Cavalleri  19 ; Epi25 Collaborative
Affiliations

The role of common genetic variation in presumed monogenic epilepsies

Ciarán Campbell et al. EBioMedicine. 2022 Jul.

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.

Keywords: DEEs; Epilepsy; Genetic diagnostics; PRS.

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Conflict of interest statement

Declaration of interests Dennis Lal received research support from Taysha Therapeutics via his institution, received consulting fees from Encoded Therapeutics and honoraria for lectures from Stoke Therapeutics. Gianpiero Cavalleri received grant funding from Janssen Pharmaceuticals and Congenica for projects not directly related to this manuscript. Ingrid Scheffer received consulting fees from Atheneum Partners, Care Beyond Diagnosis, Epilepsy Consortium, Ovid Therapeutics, UCB, Zynerba Pharmaceuticals, honoraria for lectures or presentations from Athena Diagnostics, Biocodex, BioMarin, Chiesi, Eisai, GlaxoSmithKline, Liva Nova, UCB, support to attend meeting from Biocodex, BioMarin, Eisai, GlaxoSmithKline and UCB, has two patents WO/2006/13358 and WO/2013/059884 and a pending patent WO/2009/086591, participates on the journal board of The Lancet Neurology, Progress in Epileptic Disorders series, Epilepsy Currents, Epileptic Disorders and Neurology, is on the Scientific Advisory Board of BioMarin, Chiesi, Eisai, Encoded Therapeutics, GlaxoSmithKline, Knopp Biosciences, Takeda Pharmaceuticals, UCB, Xenon Pharmaceuticals, is the non executive director of BellberryLtd and is a trial investigator for Anavex Life Sciences, Cerebral Therapeutics, Cerecin Inc, Eisai, Encoded Therapeutics, EpiMinder Inc, Epygenyx, ES-Therapeutics, GW Pharmaceuticals, Marinus Pharmaceuticals, Neurocrine BioSciences, Ovid Therapeutics, Takeda Pharmaceuticals, UCB, Ultragenyx, Xenon Pharmaceuticals, Zogenix, Zynerba Pharmaceuticals. Norman Delanty received grants or contracts from GW Pharma, Uneeg, IIP Novartis. Stefan Wolking received grants or contracts from the German Research Foundation for projects not directly related to this manuscript, honoraria for speaker fees from Angelini, support for travel from Eisai and Angelini, is the president of the German Epilepsy Society (ILAE Branch) – Commission for Epilepsy and Genetics. Yen-Chen Anne Feng is supported by the “National Taiwan University Higher Education Sprout Project (NTU-110L8810)” within the framework of the Higher Education Sprout Project by the Ministry of Education (MOE) in Taiwan. Holger Lerche received grants from the German Research Foundation, the Federal Ministry for Education and research, Else-Kröner Fresenius Foundation, Bial, Boehringer Ingelheim for projects not directly related to this manuscript, consulting fees from Bial, Eisai, UCB/Zogenix, Arvelle/Angelini Pharma, honoraria for lectures from Bial, Eisai, UCB/Zogenix, Desitin, support for attending meetings and/or travel from Bial, Eisai, UCB/Zogenix, Desitin, participated on the data safety and monitoring board of IntraBio, chaired the Genetics Commission of the ILAE. The other authors have no conflicts of interest to report.

Figures

Fig 1
Figure 1
Meta-analysis of PRS of a) ‘all epilepsy’, b) ‘Focal epilepsy’, and c) GGE. ‘FE Model’ = Fixed-effects model. Box plots show log odds ratios and standard errors.
Fig 2
Figure 2
Fixed-effects meta-analyses comparing cases with or without likely deleterious genetic variants to each other and population controls for a) ‘All epilepsy’ PRS, b) Focal PRS, and c) GGE epilepsy PRS. Log odds ratios and 95% confidence intervals are displayed in the error bars. P-values for each model are shown as numbers.
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