Genome-wide Polygenic Burden of Rare Deleterious Variants in Sudden Unexpected Death in Epilepsy
Costin Leu,
Simona Balestrini,
Bridget Maher,
Laura Hernández-Hernández,
Padhraig Gormley,
Eija Hämäläinen,
Kristin Heggeli,
Natasha Schoeler,
Jan Novy,
Joseph Willis,
Vincent Plagnol,
Rachael Ellis,
Eleanor Reavey,
Mary O'Regan,
William O. Pickrell,
Rhys H. Thomas,
Seo-Kyung Chung,
Norman Delanty,
Jacinta M. McMahon,
Stephen Malone,
Lynette G. Sadleir,
Samuel F. Berkovic,
Lina Nashef,
Sameer M. Zuberi,
Mark I. Rees,
Gianpiero L. Cavalleri,
Josemir W. Sander,
Elaine Hughes,
J. Helen Cross,
Ingrid E. Scheffer,
Aarno Palotie,
Sanjay M. Sisodiya
Affiliations
Costin Leu
NIHR University College London Hospitals Biomedical Research Centre, Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, London, UK
Simona Balestrini
NIHR University College London Hospitals Biomedical Research Centre, Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, London, UK
Bridget Maher
NIHR University College London Hospitals Biomedical Research Centre, Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, London, UK
Laura Hernández-Hernández
NIHR University College London Hospitals Biomedical Research Centre, Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, London, UK
Padhraig Gormley
Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
Eija Hämäläinen
Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland
Kristin Heggeli
NIHR University College London Hospitals Biomedical Research Centre, Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, London, UK
Natasha Schoeler
NIHR University College London Hospitals Biomedical Research Centre, Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, London, UK
Jan Novy
Department of Clinical Neurosciences, Centre Hospitalier Universitaire Vaudois (CHUV) and University of Lausanne, Lausanne, Switzerland
Joseph Willis
NIHR University College London Hospitals Biomedical Research Centre, Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, London, UK
Vincent Plagnol
University College London Genetics Institute, London, UK
Rachael Ellis
Paediatric Neurosciences Research Group, Royal Hospital for Sick Children, Glasgow, UK
Eleanor Reavey
Paediatric Neurosciences Research Group, Royal Hospital for Sick Children, Glasgow, UK
Mary O'Regan
Paediatric Neurosciences Research Group, Royal Hospital for Sick Children, Glasgow, UK
William O. Pickrell
Wales Epilepsy Research Network, Institute of Life Science, College of Medicine, Swansea University, Swansea, UK
Rhys H. Thomas
Wales Epilepsy Research Network, Institute of Life Science, College of Medicine, Swansea University, Swansea, UK
Seo-Kyung Chung
Wales Epilepsy Research Network, Institute of Life Science, College of Medicine, Swansea University, Swansea, UK
Norman Delanty
Department of Neurology, Beaumont Hospital, Dublin, Ireland
Jacinta M. McMahon
Departments of Medicine and Neurology, University of Melbourne, Austin Health, Melbourne, Australia
Stephen Malone
Department of Neurosciences, Lady Cilento Children's Hospital, Brisbane, Queensland, Australia
Lynette G. Sadleir
Department of Paediatrics, School of Medicine and Health Sciences, University of Otago, Wellington, New Zealand
Samuel F. Berkovic
Departments of Medicine and Neurology, University of Melbourne, Austin Health, Melbourne, Australia
Lina Nashef
Department of Neurology, King's College Hospital, London, UK
Sameer M. Zuberi
Paediatric Neurosciences Research Group, Royal Hospital for Sick Children, Glasgow, UK
Mark I. Rees
Wales Epilepsy Research Network, Institute of Life Science, College of Medicine, Swansea University, Swansea, UK
Gianpiero L. Cavalleri
Molecular and Cellular Therapeutics Department, Royal College of Surgeons in Ireland, Dublin, Ireland
Josemir W. Sander
NIHR University College London Hospitals Biomedical Research Centre, Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, London, UK
Elaine Hughes
Children's Neurosciences, Evelina Children's Hospital at Guys and St Thomas' NHS Foundation Trust, Kings Health Partners Academic Health Science Centre, London, UK
J. Helen Cross
UCL Institute of Child Health, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
Ingrid E. Scheffer
Departments of Medicine and Neurology, University of Melbourne, Austin Health, Melbourne, Australia
Aarno Palotie
Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
Sanjay M. Sisodiya
NIHR University College London Hospitals Biomedical Research Centre, Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, London, UK
Sudden unexpected death in epilepsy (SUDEP) represents the most severe degree of the spectrum of epilepsy severity and is the commonest cause of epilepsy-related premature mortality. The precise pathophysiology and the genetic architecture of SUDEP remain elusive. Aiming to elucidate the genetic basis of SUDEP, we analysed rare, protein-changing variants from whole-exome sequences of 18 people who died of SUDEP, 87 living people with epilepsy and 1479 non-epilepsy disease controls. Association analysis revealed a significantly increased genome-wide polygenic burden per individual in the SUDEP cohort when compared to epilepsy (P = 5.7 × 10−3) and non-epilepsy disease controls (P = 1.2 × 10−3). The polygenic burden was driven both by the number of variants per individual, and over-representation of variants likely to be deleterious in the SUDEP cohort. As determined by this study, more than a thousand genes contribute to the observed polygenic burden within the framework of this study. Subsequent gene-based association analysis revealed five possible candidate genes significantly associated with SUDEP or epilepsy, but no one single gene emerges as common to the SUDEP cases. Our findings provide further evidence for a genetic susceptibility to SUDEP, and suggest an extensive polygenic contribution to SUDEP causation. Thus, an overall increased burden of deleterious variants in a highly polygenic background might be important in rendering a given individual more susceptible to SUDEP. Our findings suggest that exome sequencing in people with epilepsy might eventually contribute to generating SUDEP risk estimates, promoting stratified medicine in epilepsy, with the eventual aim of reducing an individual patient's risk of SUDEP.
