Evidence map›Paper›PMID 26501104›Full record

ArticleEBioMedicine2015

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 and 22 more

Open access · goldAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in EBioMedicine, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers, 1 of them a synthesis that pooled it.

0numbers the graph read from it
0cells of the map it votes in
25citing papers in PubMed, 1 pooled it
4.2field-weighted citation impact, top 6% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

25 citing papers in PubMed, 1 synthesis or guideline pooled it, 84 citations in OpenAlex.

  1. Pooled it
  2. Heterogeneity of monogenic epilepsy in loci, phenotypes, and treatment approaches.Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology · 2026
    Review
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  15. Cardiac arrhythmias in Dravet syndrome: an observational multicenter study.Annals of clinical and translational neurology · 2020
    Observational
  16. Article
  17. Review
  18. Update on the Genetic Basis of Sudden Unexpected Death in Epilepsy.International journal of molecular sciences · 2019
    Review
  19. Article
  20. Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

32 authors at 16 institutions in 7 countries.

Costin LeuNIHR University College London Hospitals Biomedical Research Centre, Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, London, UK.
Simona BalestriniNIHR 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.
Bridget MaherNIHR 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 Hernández-HernándezNIHR 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.
Padhraig GormleyAnalytic 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.
Eija HämäläinenInstitute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland.
Kristin HeggeliNIHR University College London Hospitals Biomedical Research Centre, Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, London, UK.
Natasha SchoelerNIHR University College London Hospitals Biomedical Research Centre, Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, London, UK.
Jan NovyDepartment of Clinical Neurosciences, Centre Hospitalier Universitaire Vaudois (CHUV) and University of Lausanne, Lausanne, Switzerland.
Joseph WillisNIHR University College London Hospitals Biomedical Research Centre, Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, London, UK.
Vincent PlagnolUniversity College London Genetics Institute, London, UK.
Rachael EllisPaediatric Neurosciences Research Group, Royal Hospital for Sick Children, Glasgow, UK ; West of Scotland Genetic Services, Southern General Hospital, Glasgow, UK.
Eleanor ReaveyPaediatric Neurosciences Research Group, Royal Hospital for Sick Children, Glasgow, UK ; West of Scotland Genetic Services, Southern General Hospital, Glasgow, UK.
Mary O'ReganPaediatric Neurosciences Research Group, Royal Hospital for Sick Children, Glasgow, UK.
William O PickrellWales Epilepsy Research Network, Institute of Life Science, College of Medicine, Swansea University, Swansea, UK.
Rhys H ThomasWales Epilepsy Research Network, Institute of Life Science, College of Medicine, Swansea University, Swansea, UK.
Seo-Kyung ChungWales Epilepsy Research Network, Institute of Life Science, College of Medicine, Swansea University, Swansea, UK.
Norman DelantyDepartment of Neurology, Beaumont Hospital, Dublin, Ireland.
Jacinta M McMahonDepartments of Medicine and Neurology, University of Melbourne, Austin Health, Melbourne, Australia.
Stephen MaloneDepartment of Neurosciences, Lady Cilento Children's Hospital, Brisbane, Queensland, Australia.
Lynette G SadleirDepartment of Paediatrics, School of Medicine and Health Sciences, University of Otago, Wellington, New Zealand.
Samuel F BerkovicDepartments of Medicine and Neurology, University of Melbourne, Austin Health, Melbourne, Australia.
Lina NashefDepartment of Neurology, King's College Hospital, London, UK.
Sameer M ZuberiPaediatric Neurosciences Research Group, Royal Hospital for Sick Children, Glasgow, UK ; School of Medicine, University of Glasgow, Glasgow, UK.
Mark I ReesWales Epilepsy Research Network, Institute of Life Science, College of Medicine, Swansea University, Swansea, UK.
Gianpiero L CavalleriMolecular and Cellular Therapeutics Department, Royal College of Surgeons in Ireland, Dublin, Ireland.
Josemir W SanderNIHR 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.
Elaine HughesChildren'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 CrossUCL Institute of Child Health, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK ; Young Epilepsy, Lingfield, UK.
Ingrid E SchefferDepartments 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.
Aarno PalotieAnalytic 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.
Sanjay M SisodiyaNIHR 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.
UCL Biomedical Research Centre · GBRoyal Hospital for Children · GBSwansea University · GBBroad Institute · USThe University of Melbourne · AUBeaumont Hospital · IEBoston Children's Hospital · USChildren's Health Queensland Hospital and Health Service · AUGreat Ormond Street Hospital for Children NHS Foundation Trust · GBKing's College Hospital · GBRoyal Children's Hospital · AURoyal College of Surgeons in Ireland · IEUniversity College London · GBUniversity Hospital of Lausanne · CHUniversity of Helsinki · FIUniversity of Otago · NZ

Funding

Wellcome Trust 104033
6 · The paper itself

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.

Indexed as

Genetic VariationAdultCause of DeathDeath, SuddenEpilepsyExomeFemaleGenetic Association StudiesGenetic Predisposition to DiseaseGenome-Wide Association StudyHumansMaleMultifactorial InheritanceRisk FactorsSequence Analysis, DNASeverity of Illness IndexAED, anti-epileptic drugAssociationBurdenDeathEpilepsyMAF, minor allele frequencyMortalityn, numberQC, quality controlSeveritySUDEP, sudden unexpected death in epilepsyWES, whole-exome sequencing

Identifiers

PMID26501104
PMCPMC4588398
OpenAlexW1853663395

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.