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

doi:10.1016/j.ebiom.2015.07.005

Genome-wide Polygenic Burden of Rare Deleterious Variants in Sudden Unexpected Death in Epilepsy

EBioMedicine. 2015 Jul 10;2(9):1063-70. doi: 10.1016/j.ebiom.2015.07.005. eCollection 2015 Sep.

Authors

Costin Leu¹, Simona Balestrini², Bridget Maher³, Laura Hernández-Hernández³, Padhraig Gormley⁴, Eija Hämäläinen⁵, Kristin Heggeli¹, Natasha Schoeler¹, Jan Novy⁶, Joseph Willis¹, Vincent Plagnol⁷, Rachael Ellis⁸, Eleanor Reavey⁸, Mary O'Regan⁹, William O Pickrell¹⁰, Rhys H Thomas¹⁰, Seo-Kyung Chung¹⁰, Norman Delanty¹¹, Jacinta M McMahon¹², Stephen Malone¹³, Lynette G Sadleir¹⁴, Samuel F Berkovic¹², Lina Nashef¹⁵, Sameer M Zuberi¹⁶, Mark I Rees¹⁰, Gianpiero L Cavalleri¹⁷, Josemir W Sander³, Elaine Hughes¹⁸, J Helen Cross¹⁹, Ingrid E Scheffer²⁰, Aarno Palotie²¹, Sanjay M Sisodiya³

Affiliations

¹ NIHR University College London Hospitals Biomedical Research Centre, Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, London, UK.
² 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.
³ 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.
⁴ 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.
⁵ Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland.
⁶ Department of Clinical Neurosciences, Centre Hospitalier Universitaire Vaudois (CHUV) and University of Lausanne, Lausanne, Switzerland.
⁷ University College London Genetics Institute, London, UK.
⁸ Paediatric Neurosciences Research Group, Royal Hospital for Sick Children, Glasgow, UK ; West of Scotland Genetic Services, Southern General Hospital, Glasgow, UK.
⁹ Paediatric Neurosciences Research Group, Royal Hospital for Sick Children, Glasgow, UK.
¹⁰ Wales Epilepsy Research Network, Institute of Life Science, College of Medicine, Swansea University, Swansea, UK.
¹¹ Department of Neurology, Beaumont Hospital, Dublin, Ireland.
¹² Departments of Medicine and Neurology, University of Melbourne, Austin Health, Melbourne, Australia.
¹³ Department of Neurosciences, Lady Cilento Children's Hospital, Brisbane, Queensland, Australia.
¹⁴ Department of Paediatrics, School of Medicine and Health Sciences, University of Otago, Wellington, New Zealand.
¹⁵ Department of Neurology, King's College Hospital, London, UK.
¹⁶ Paediatric Neurosciences Research Group, Royal Hospital for Sick Children, Glasgow, UK ; School of Medicine, University of Glasgow, Glasgow, UK.
¹⁷ Molecular and Cellular Therapeutics Department, Royal College of Surgeons in Ireland, Dublin, Ireland.
¹⁸ Children's Neurosciences, Evelina Children's Hospital at Guys and St Thomas' NHS Foundation Trust, Kings Health Partners Academic Health Science Centre, London, UK.
¹⁹ UCL Institute of Child Health, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK ; Young Epilepsy, Lingfield, UK.
²⁰ 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.
²¹ 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.

Abstract

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.

Keywords: 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.

MeSH terms

Adult
Cause of Death
Death, Sudden
Epilepsy / genetics*
Epilepsy / mortality
Epilepsy / pathology
Exome / genetics
Female
Genetic Association Studies / methods
Genetic Predisposition to Disease / genetics
Genetic Variation*
Genome-Wide Association Study / methods*
Humans
Male
Multifactorial Inheritance / genetics*
Risk Factors
Sequence Analysis, DNA / methods
Severity of Illness Index

Grants and funding

104033/Wellcome Trust/United Kingdom