Genome-wide Polygenic Burden of Rare Deleterious Variants in Sudden Unexpected Death in Epilepsy.
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.
NIHR University College London Hospitals Biomedical Research Centre, Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, London, UK.
Costin
C
Leu
NIHR University College London Hospitals Biomedical Research Centre, Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, London, UK ; The Epilepsy Society, Chalfont-St-Peter, Bucks, UK ; Neuroscience Department, Polytechnic University of Marche, Ancona, Italy.
Simona
S
Balestrini
NIHR University College London Hospitals Biomedical Research Centre, Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, London, UK ; The Epilepsy Society, Chalfont-St-Peter, Bucks, UK.
Bridget
B
Maher
NIHR University College London Hospitals Biomedical Research Centre, Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, London, UK ; The Epilepsy Society, Chalfont-St-Peter, Bucks, UK.
Laura
L
Hernández-Hernández
Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA ; Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA ; The Stanley Center for Psychiatric Research, The Broad Institute of MIT and Harvard, Cambridge, MA, USA ; Psychiatric & Neurodevelopmental Genetics Unit, Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA.
Padhraig
P
Gormley
Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland.
Eija
E
Hämäläinen
NIHR University College London Hospitals Biomedical Research Centre, Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, London, UK.
Kristin
K
Heggeli
NIHR University College London Hospitals Biomedical Research Centre, Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, London, UK.
Natasha
N
Schoeler
Department of Clinical Neurosciences, Centre Hospitalier Universitaire Vaudois (CHUV) and University of Lausanne, Lausanne, Switzerland.
Jan
J
Novy
NIHR University College London Hospitals Biomedical Research Centre, Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, London, UK.
Joseph
J
Willis
University College London Genetics Institute, London, UK.
Vincent
V
Plagnol
Paediatric Neurosciences Research Group, Royal Hospital for Sick Children, Glasgow, UK ; West of Scotland Genetic Services, Southern General Hospital, Glasgow, UK.
Rachael
R
Ellis
Paediatric Neurosciences Research Group, Royal Hospital for Sick Children, Glasgow, UK ; West of Scotland Genetic Services, Southern General Hospital, Glasgow, UK.
Eleanor
E
Reavey
Paediatric Neurosciences Research Group, Royal Hospital for Sick Children, Glasgow, UK.
Mary
M
O'Regan
Wales Epilepsy Research Network, Institute of Life Science, College of Medicine, Swansea University, Swansea, UK.
William O
WO
Pickrell
Wales Epilepsy Research Network, Institute of Life Science, College of Medicine, Swansea University, Swansea, UK.
Rhys H
RH
Thomas
Wales Epilepsy Research Network, Institute of Life Science, College of Medicine, Swansea University, Swansea, UK.
Seo-Kyung
SK
Chung
Department of Neurology, Beaumont Hospital, Dublin, Ireland.
Norman
N
Delanty
Departments of Medicine and Neurology, University of Melbourne, Austin Health, Melbourne, Australia.
Jacinta M
JM
McMahon
Department of Neurosciences, Lady Cilento Children's Hospital, Brisbane, Queensland, Australia.
Stephen
S
Malone
Department of Paediatrics, School of Medicine and Health Sciences, University of Otago, Wellington, New Zealand.
Lynette G
LG
Sadleir
Departments of Medicine and Neurology, University of Melbourne, Austin Health, Melbourne, Australia.
Samuel F
SF
Berkovic
Department of Neurology, King's College Hospital, London, UK.
Lina
L
Nashef
Paediatric Neurosciences Research Group, Royal Hospital for Sick Children, Glasgow, UK ; School of Medicine, University of Glasgow, Glasgow, UK.
Sameer M
SM
Zuberi
Wales Epilepsy Research Network, Institute of Life Science, College of Medicine, Swansea University, Swansea, UK.
Mark I
MI
Rees
Molecular and Cellular Therapeutics Department, Royal College of Surgeons in Ireland, Dublin, Ireland.
Gianpiero L
GL
Cavalleri
NIHR University College London Hospitals Biomedical Research Centre, Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, London, UK ; The Epilepsy Society, Chalfont-St-Peter, Bucks, UK.
Josemir W
JW
Sander
Children's Neurosciences, Evelina Children's Hospital at Guys and St Thomas' NHS Foundation Trust, Kings Health Partners Academic Health Science Centre, London, UK.
Elaine
E
Hughes
UCL Institute of Child Health, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK ; Young Epilepsy, Lingfield, UK.
J
J
Helen Cross
Departments of Medicine and Neurology, University of Melbourne, Austin Health, Melbourne, Australia ; Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Parkville, Australia ; Florey Institute of Neuroscience and Mental Health, Melbourne, Australia.
Ingrid E
IE
Scheffer
Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA ; Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA ; The Stanley Center for Psychiatric Research, The Broad Institute of MIT and Harvard, Cambridge, MA, USA ; Psychiatric & Neurodevelopmental Genetics Unit, Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA ; Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland ; Department of Neurology, Massachusetts General Hospital, Boston, MA, USA.
Aarno
A
Palotie
NIHR University College London Hospitals Biomedical Research Centre, Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, London, UK ; The Epilepsy Society, Chalfont-St-Peter, Bucks, UK.
Sanjay M
SM
Sisodiya
D000328:Adult; D002423:Cause of Death; D003645:Death, Sudden; D004827:Epilepsy / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D059472:Exome / Q000235:genetics; D005260:Female; D056726:Genetic Association Studies / Q000379:methods; D020022:Genetic Predisposition to Disease / Q000235:genetics; D014644:Genetic Variation; D055106:Genome-Wide Association Study / Q000379:methods*; D006801:Humans; D008297:Male; D020412:Multifactorial Inheritance / Q000235:genetics*; D012307:Risk Factors; D017422:Sequence Analysis, DNA / Q000379:methods; D012720:Severity of Illness Index
AED, anti-epileptic drug; Association; Burden; Death; Epilepsy; MAF, minor allele frequency; Mortality; QC, quality control; SUDEP, sudden unexpected death in epilepsy; Severity; WES, whole-exome sequencing; n, number