The role of common genetic variation in presumed monogenic epilepsies
Ciarán Campbell,
Costin Leu,
Yen-Chen Anne Feng,
Stefan Wolking,
Claudia Moreau,
Colin Ellis,
Shiva Ganesan,
Helena Martins,
Karen Oliver,
Isabelle Boothman,
Katherine Benson,
Anne Molloy,
Lawrence Brody,
Jacques L. Michaud,
Fadi F. Hamdan,
Berge A. Minassian,
Holger Lerche,
Ingrid E. Scheffer,
Sanjay Sisodiya,
Simon Girard,
Patrick Cosette,
Norman Delanty,
Dennis Lal,
Gianpiero L. Cavalleri
Affiliations
Ciarán Campbell
The SFI FutureNeuro Research Centre, RCSI Dublin, Republic of Ireland; The School of Pharmacy and Biomolecular Sciences, RCSI Dublin, Republic of Ireland
Costin Leu
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 M.I.T, Cambridge, MA, United States of America
Yen-Chen Anne Feng
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
Stefan Wolking
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 Montréal, Montréal, Canada
Claudia Moreau
Centre Intersectoriel en Santé Durable, Université du Québec à Chicoutimi, Saguenay, Canada
Colin Ellis
Department of Neurology, University of Pennsylvania, Philadelphia, PA, USA
Shiva Ganesan
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, Philadelphia, PA 19104, USA
Helena Martins
UCL Queen Square Institute of Neurology, London WC1N 3BG and Chalfont Centre for Epilepsy, Bucks, United Kingdom
Karen Oliver
Epilepsy Research Centre, Department of Medicine, The University of Melbourne, Melbourne, Victoria, Australia
Isabelle Boothman
The SFI FutureNeuro Research Centre, RCSI Dublin, Republic of Ireland; The School of Pharmacy and Biomolecular Sciences, RCSI Dublin, Republic of Ireland
Katherine Benson
The SFI FutureNeuro Research Centre, RCSI Dublin, Republic of Ireland; The School of Pharmacy and Biomolecular Sciences, RCSI Dublin, Republic of Ireland
Anne Molloy
Department of Medical Gerontology, School of Medicine, Trinity College Dublin, Dublin 2, Republic of Ireland
Lawrence Brody
Division of Intramural Research, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA
Jacques L. Michaud
CHU Sainte-Justine Research Center, Montreal, Quebec, Canada
Fadi F. Hamdan
CHU Sainte-Justine Research Center, Montreal, Quebec, Canada
Berge A. Minassian
Department of Pediatrics, Hospital for Sick Children and University of Toronto, Toronto, Canada
Holger Lerche
Department of Neurology & Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany
Ingrid E. Scheffer
University of Melbourne, Austin and Royal Children's Hospitals, Melbourne, Australia; Florey Institute and Murdoch Children's Research Institute, Melbourne, Australia
Sanjay Sisodiya
UCL Queen Square Institute of Neurology, London WC1N 3BG and Chalfont Centre for Epilepsy, Bucks, United Kingdom
Simon Girard
Centre Intersectoriel en Santé Durable, Université du Québec à Chicoutimi, Saguenay, Canada
Patrick Cosette
Department of Medicine, Neurology Division, Centre Hospitalier de l'Université de Montréal, Montreal, Quebec, Canada
Norman Delanty
The School of Pharmacy and Biomolecular Sciences, RCSI Dublin, Republic of Ireland; Department of Neurology, Beaumont Hospital, Dublin, Republic of Ireland
Dennis Lal
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, Cleveland, OH, USA; Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany
Gianpiero L. Cavalleri
The SFI FutureNeuro Research Centre, RCSI Dublin, Republic of Ireland; The School of Pharmacy and Biomolecular Sciences, RCSI Dublin, Republic of Ireland; Corresponding author.
Summary: 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.
