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The role of common genetic variation in presumed monogenic epilepsies.
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; 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.
Afiliação
  • Campbell C; The SFI FutureNeuro Research Centre, RCSI Dublin, Republic of Ireland; The School of Pharmacy and Biomolecular Sciences, RCSI Dublin, Republic of Ireland.
  • Leu C; Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, United States of America; UCL Queen Square Institute of Neurology, London WC1N 3BG and Chalfont Centre for Epilepsy, Bucks, United Kingdom; Stanley Center for Psychiatric Research, Broad Institute of Harvard and
  • Feng YA; Stanley Center for Psychiatric Research, Broad Institute of Harvard and M.I.T, Cambridge, MA, United States of America; Division of Biostatistics, Institute of Epidemiology and Preventive Medicine, National Taiwan University, Taipei, Taiwan.
  • Wolking S; Department of Neurology & Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany; Department of Epileptology and Neurology, University of Aachen, Aachen, Germany; Axe Neurosciences, Centre de recherche de l'Université de Montréal, Université de Mont
  • Moreau C; Centre Intersectoriel en Santé Durable, Université du Québec à Chicoutimi, Saguenay, Canada.
  • Ellis C; Department of Neurology, University of Pennsylvania, Philadelphia, PA, USA.
  • Ganesan S; Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Biomedical and Health Informatics (DBHi), Children's Hospital of Philadelphia, Philadelphia, PA 19146, USA; The Epilepsy NeuroGenetics Initiative (ENGIN), Children's Hospital of Philadelphia, Phila
  • Martins H; UCL Queen Square Institute of Neurology, London WC1N 3BG and Chalfont Centre for Epilepsy, Bucks, United Kingdom.
  • Oliver K; Epilepsy Research Centre, Department of Medicine, The University of Melbourne, Melbourne, Victoria, Australia.
  • Boothman I; The SFI FutureNeuro Research Centre, RCSI Dublin, Republic of Ireland; The School of Pharmacy and Biomolecular Sciences, RCSI Dublin, Republic of Ireland.
  • Benson K; The SFI FutureNeuro Research Centre, RCSI Dublin, Republic of Ireland; The School of Pharmacy and Biomolecular Sciences, RCSI Dublin, Republic of Ireland.
  • Molloy A; Department of Medical Gerontology, School of Medicine, Trinity College Dublin, Dublin 2, Republic of Ireland.
  • Brody L; Division of Intramural Research, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
  • Michaud JL; CHU Sainte-Justine Research Center, Montreal, Quebec, Canada.
  • Hamdan FF; CHU Sainte-Justine Research Center, Montreal, Quebec, Canada.
  • Minassian BA; Department of Pediatrics, Hospital for Sick Children and University of Toronto, Toronto, Canada.
  • Lerche H; Department of Neurology & Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
  • Scheffer IE; University of Melbourne, Austin and Royal Children's Hospitals, Melbourne, Australia; Florey Institute and Murdoch Children's Research Institute, Melbourne, Australia.
  • Sisodiya S; UCL Queen Square Institute of Neurology, London WC1N 3BG and Chalfont Centre for Epilepsy, Bucks, United Kingdom.
  • Girard S; Centre Intersectoriel en Santé Durable, Université du Québec à Chicoutimi, Saguenay, Canada.
  • Cosette P; Department of Medicine, Neurology Division, Centre Hospitalier de l'Université de Montréal, Montreal, Quebec, Canada.
  • Delanty N; The School of Pharmacy and Biomolecular Sciences, RCSI Dublin, Republic of Ireland; Department of Neurology, Beaumont Hospital, Dublin, Republic of Ireland.
  • Lal D; Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, United States of America; Stanley Center for Psychiatric Research, Broad Institute of Harvard and M.I.T, Cambridge, MA, United States of America; Epilepsy Center, Neurological Institute, Cleveland Clinic, Clevela
  • Cavalleri GL; The SFI FutureNeuro Research Centre, RCSI Dublin, Republic of Ireland; The School of Pharmacy and Biomolecular Sciences, RCSI Dublin, Republic of Ireland. Electronic address: gcavalleri@rcsi.ie.
EBioMedicine ; 81: 104098, 2022 Jul.
Article em En | MEDLINE | ID: mdl-35679801
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.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Epilepsia Generalizada / Deficiência Intelectual Idioma: En Ano de publicação: 2022 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Epilepsia Generalizada / Deficiência Intelectual Idioma: En Ano de publicação: 2022 Tipo de documento: Article