SUDEP risk is influenced by longevity genomics: a polygenic risk score studyResearch in context
Helena Martins,
James D. Mills,
Susanna Pagni,
Medine I. Gulcebi,
Angeliki Vakrinou,
Patrick B. Moloney,
Lisa M. Clayton,
Ravishankara Bellampalli,
Hannah Stamberger,
Sarah Weckhuysen,
Pasquale Striano,
Federico Zara,
Richard D. Bagnall,
Rebekah V. Harris,
Kate M. Lawrence,
Lynette G. Sadleir,
Douglas E. Crompton,
Daniel Friedman,
Juliana Laze,
Ling Li,
Samuel F. Berkovic,
Christopher Semsarian,
Ingrid E. Scheffer,
Orrin Devinsky,
Karoline Kuchenbaecker,
Simona Balestrini,
Sanjay M. Sisodiya
Affiliations
Helena Martins
University College London Queen Square Institute of Neurology, London, WC1N 3BG, UK; Chalfont Centre for Epilepsy, Chalfont St Peter, SL9 0RJ, UK
James D. Mills
University College London Queen Square Institute of Neurology, London, WC1N 3BG, UK; Chalfont Centre for Epilepsy, Chalfont St Peter, SL9 0RJ, UK; Department of (Neuro)Pathology, Amsterdam Neuroscience, Amsterdam UMC Location University of Amsterdam, Meibergdreef 9, Amsterdam, the Netherlands
Susanna Pagni
University College London Queen Square Institute of Neurology, London, WC1N 3BG, UK; Chalfont Centre for Epilepsy, Chalfont St Peter, SL9 0RJ, UK
Medine I. Gulcebi
University College London Queen Square Institute of Neurology, London, WC1N 3BG, UK; Chalfont Centre for Epilepsy, Chalfont St Peter, SL9 0RJ, UK; Department of Medical Pharmacology, Marmara University School of Medicine, Istanbul, Turkey
Angeliki Vakrinou
University College London Queen Square Institute of Neurology, London, WC1N 3BG, UK; Chalfont Centre for Epilepsy, Chalfont St Peter, SL9 0RJ, UK
Patrick B. Moloney
University College London Queen Square Institute of Neurology, London, WC1N 3BG, UK; Chalfont Centre for Epilepsy, Chalfont St Peter, SL9 0RJ, UK
Lisa M. Clayton
University College London Queen Square Institute of Neurology, London, WC1N 3BG, UK; Chalfont Centre for Epilepsy, Chalfont St Peter, SL9 0RJ, UK
Ravishankara Bellampalli
University College London Queen Square Institute of Neurology, London, WC1N 3BG, UK; Chalfont Centre for Epilepsy, Chalfont St Peter, SL9 0RJ, UK
Hannah Stamberger
Applied & Translational Neurogenomics Group, VIB Center for Molecular Neurology, VIB, Antwerp, Belgium; Translational Neurosciences, Faculty of Medicine and Health Science, University of Antwerp, Antwerp, Belgium; Department of Neurology, Antwerp University Hospital, Antwerp, Belgium
Sarah Weckhuysen
Applied & Translational Neurogenomics Group, VIB Center for Molecular Neurology, VIB, Antwerp, Belgium; Translational Neurosciences, Faculty of Medicine and Health Science, University of Antwerp, Antwerp, Belgium; Department of Neurology, Antwerp University Hospital, Antwerp, Belgium
Pasquale Striano
IRCCS G. Gaslini, Pediatric Neurology and Muscular Diseases Unit, Full Member of ERN-EPICARE, Genova, Italy; Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genova, Genova, Italy
Molecular Cardiology Group at Centenary Institute, The University of Sydney, Sydney, New South Wales, 2050, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, 2050, Australia
Rebekah V. Harris
Epilepsy Research Centre, The University of Melbourne, Austin Health, Heidelberg, Victoria, 3084, Australia
Kate M. Lawrence
Epilepsy Research Centre, The University of Melbourne, Austin Health, Heidelberg, Victoria, 3084, Australia
Lynette G. Sadleir
Department of Paediatrics and Child Health, University of Otago, Wellington, New Zealand
Douglas E. Crompton
Epilepsy Research Centre, The University of Melbourne, Austin Health, Heidelberg, Victoria, 3084, Australia; Department of Neurology, Northern Health, Epping, Victoria, Australia
Daniel Friedman
Department of Neurology, NYU Grossman School of Medicine, New York, NY, 10016, United States
Juliana Laze
Department of Neurology, NYU Grossman School of Medicine, New York, NY, 10016, United States
Ling Li
Department of Pediatrics, University of Maryland School of Medicine, MD, 21223, United States; Office of the Chief Medical Examiner (OCME), Baltimore, MD, 21201, United States
Samuel F. Berkovic
Epilepsy Research Centre, The University of Melbourne, Austin Health, Heidelberg, Victoria, 3084, Australia
Christopher Semsarian
Molecular Cardiology Group at Centenary Institute, The University of Sydney, Sydney, New South Wales, 2050, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, 2050, Australia
Ingrid E. Scheffer
Epilepsy Research Centre, The University of Melbourne, Austin Health, Heidelberg, Victoria, 3084, Australia; Florey and Murdoch Children's Research Institutes, Victoria, 3052, Australia; Department of Paediatrics, The University of Melbourne, Royal Children's Hospital, Parkville, Victoria, 3052, Australia
Orrin Devinsky
Department of Neurology, NYU Grossman School of Medicine, New York, NY, 10016, United States
Karoline Kuchenbaecker
University College London Division of Psychiatry, Maple House, London, W1T 7BN, UK
Simona Balestrini
University College London Queen Square Institute of Neurology, London, WC1N 3BG, UK; Chalfont Centre for Epilepsy, Chalfont St Peter, SL9 0RJ, UK; Department of Neuroscience and Medical Genetics, Meyer Children's Hospital IRCSS, University of Florence, 50139, Florence, Italy
Sanjay M. Sisodiya
University College London Queen Square Institute of Neurology, London, WC1N 3BG, UK; Chalfont Centre for Epilepsy, Chalfont St Peter, SL9 0RJ, UK; Corresponding author. Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, Box 29, Queen Square, London, WC1N 3BG, UK.
Summary: Background: Sudden Unexpected Death in Epilepsy (SUDEP) is a rare and tragic outcome in epilepsy, identified by those with the condition as their most serious concern. Although several clinical factors are associated with elevated SUDEP risk, mechanisms underlying SUDEP are poorly understood, making individual risk prediction challenging, especially early in the disease course. We hypothesised that common genetic variation contributes to SUDEP risk. Methods: Genetic data from people who had succumbed to SUDEP was compared to data from people with epilepsy who had not succumbed to SUDEP and from healthy controls. Polygenic risk scores (PRSs) for longevity, intelligence and epilepsy were compared across cohorts. Reactome pathways and gene ontology terms implicated by the contributing single nucleotide polymorphisms (SNPs) were explored. In the subset of SUDEP cases with the necessary data available, a risk score was calculated using an existing risk prediction tool (SUDEP-3); the added value to this prediction of SNP-based genomic information was evaluated. Findings: Only European-ancestry participants were included. 161 SUDEP cases were compared to 768 cases with epilepsy and 1153 healthy controls. PRS for longevity was significantly reduced in SUDEP cases compared to disease (P = 0·0096) and healthy controls (P = 0·0016), as was PRS for intelligence (SUDEP cases compared to disease (P = 0·0073) and healthy controls (P = 0·00024)). The PRS for epilepsy did not differ between SUDEP cases and disease controls (P = 0·76). SNP-determined pathway and gene ontology analysis highlighted those related to inter-neuronal communication as amongst the most enriched in SUDEP. Addition of PRS for longevity and intelligence to SUDEP-3 scores improved risk prediction in a subset of cases (38) and controls (703), raising the area-under-the-curve in a receiver-operator characteristic from 0·699 using SUDEP-3 alone to 0·913 when PRSs were added. Interpretation: Common genetic variation contributes to SUDEP risk, offering new approaches to improve risk prediction and to understand underlying mechanisms. Funding: The Amelia Roberts Fund; CURE Epilepsy; Epilepsy Society, UK; Finding A Cure for Epilepsy and Seizures (FACES).
