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

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.

PMID: 26501104
PMCID: PMC4588398
DOI: 10.1016/j.ebiom.2015.07.005

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

Costin Leu et al. EBioMedicine. 2015.

. 2015 Jul 10;2(9):1063-70.

doi: 10.1016/j.ebiom.2015.07.005. eCollection 2015 Sep.

Authors

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.

PMID: 26501104
PMCID: PMC4588398
DOI: 10.1016/j.ebiom.2015.07.005

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.

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Figures

**Fig. 1**
Individual-level quality control flowchart for the SUDEP, epilepsy control, and non-epilepsy disease control samples used in this study. Abbreviations: WES, whole-exome sequencing; SUDEP, sudden unexpected death in epilepsy.

**Fig. 2**
Violin plots of the burden score and variant number per individual. Plotted are the per-individual burden scores (A) and the number of variants per individual (B) of each test group. A violin plot is a box plot with the width of the box proportional to the estimated density of the observed data (proportion of cases with given ordinate value). The maximum density of the group-specific data distribution is indicated by the largest width of the violins. The density trace is plotted symmetrically to the left and the right of the box plot for better visualization. All violins have the same fixed maximum width. The white dot is the median, the thick black vertical bar represents the interquartile range (IQR), and the thin black vertical bar represents 95% confidence intervals.

See this image and copyright information in PMC

References

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

Affiliations

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

Authors

Affiliations

Abstract

Figures

References

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Medical

Research Materials