Exome sequencing of 20,979 individuals with epilepsy reveals shared and distinct ultra-rare genetic risk across disorder subtypes
Status PubMed-not-MEDLINE Language English Country United States Media electronic
Document type Journal Article, Preprint
Grant support
UM1 HG008895
NHGRI NIH HHS - United States
MR/S02638X/1
Medical Research Council - United Kingdom
R03 NS108145
NINDS NIH HHS - United States
U01 HG009088
NHGRI NIH HHS - United States
R01 MH110555
NIMH NIH HHS - United States
R01 NS106104
NINDS NIH HHS - United States
PubMed
36865150
PubMed Central
PMC9980234
DOI
10.1101/2023.02.22.23286310
PII: 2023.02.22.23286310
Knihovny.cz E-resources
- Publication type
- Journal Article MeSH
- Preprint MeSH
Identifying genetic risk factors for highly heterogeneous disorders like epilepsy remains challenging. Here, we present the largest whole-exome sequencing study of epilepsy to date, with >54,000 human exomes, comprising 20,979 deeply phenotyped patients from multiple genetic ancestry groups with diverse epilepsy subtypes and 33,444 controls, to investigate rare variants that confer disease risk. These analyses implicate seven individual genes, three gene sets, and four copy number variants at exome-wide significance. Genes encoding ion channels show strong association with multiple epilepsy subtypes, including epileptic encephalopathies, generalized and focal epilepsies, while most other gene discoveries are subtype-specific, highlighting distinct genetic contributions to different epilepsies. Combining results from rare single nucleotide/short indel-, copy number-, and common variants, we offer an expanded view of the genetic architecture of epilepsy, with growing evidence of convergence among different genetic risk loci on the same genes. Top candidate genes are enriched for roles in synaptic transmission and neuronal excitability, particularly postnatally and in the neocortex. We also identify shared rare variant risk between epilepsy and other neurodevelopmental disorders. Our data can be accessed via an interactive browser, hopefully facilitating diagnostic efforts and accelerating the development of follow-up studies.
Alberta Children's Hospital Research Institute University of Calgary Calgary Alberta Canada
Applied and Translational Neurogenomics Group VIB Center for Molecular Neurology VIB Antwerp Belgium
Bezmialem Vakif University Institute of Life Sciences and Biotechnology Istanbul Turkey
Bonifatius Hospital Lingen Neuropediatrics Wilhelmstrasse 13 49808 Lingen Germany
Center for Genomic Medicine Massachusetts General Hospital Boston MA USA
Centre for Medical Genetics Vilnius University Hospital Santaros Klinikos Vilnius Lithuania
Chalfont Centre for Epilepsy Chalfont St Peter Buckinghamshire SL9 0RJ UK
Child Neurology New Childreńs Hospital Helsinki Finland
Cincinnati Children's Hospital Medical Center Cincinnati Ohio USA
Citizens United for Research in Epilepsy Chicago Illinois USA
Cleveland Clinic Epilepsy Center Neurological Institute Cleveland Clinic Cleveland OH 44195 USA
Clinical Neurophysiology and Epileptology Department Timone Hospital Marseille France
Clinical Research Unit Cumming School of Medicine University of Calgary Calgary Alberta Canada
Cyprus Institute of Neurology and Genetics Nicosia Cyprus
Data Sciences Platform Broad Institute of MIT and Harvard Cambridge MA USA
Department of Biology University of Melbourne Parkville 3010 Australia
Department of Biomedical and Neuromotor Sciences University of Bologna Bologna Italy
Department of Biomedical Informatics Vanderbilt University Medical Center Nashville TN USA
Department of Biomedical Sciences Cooper Medical School of Rowan University Camden NJ 08103 USA
Department of Child Neurology Istanbul Faculty of Medicine Istanbul University Istanbul Turkey
Department of Child Neurology Medical School Dokuz Eylul University Izmir Turkey
Department of Child Neurology Medical School Kocaeli University Kocaeli Turkey
Department of Child Neurology Medical School Marmara University Istanbul Turkey
Department of Clinical Neurophysiology Lille University Medical Center EA 1046 University of Lille
Department of Clinical Neurosciences Centre Hospitalo Universitaire Vaudois Lausanne Switzerland
Department of Clinical Sciences Neurosciences Umeå University Umeå Sweden
Department of Epidemiology and Global Health Umeå University Umeå Sweden
Department of Epileptology University Hospital Freiburg Freiburg Germany
Department of Epileptology University of Bonn Medical Centre Bonn 53127 Germany
Department of Genetics Harvard Medical School Boston MA USA
Department of Medical Genetics Hospices Civils de Lyon and University of Lyon Lyon France
Department of Medicine and Therapeutics Chinese University of Hong Kong Hong Kong China
Department of Medicine Tseung Kwan O Hospital Hong Kong
Department of Medicine University of Melbourne Royal Melbourne Hospital Parkville 3050 Australia
Department of Molecular Biology and Genetics Bogaziçi University Istanbul Turkey
Department of NEUROFARBA University of Florence Florence Italy
Department of Neurology American University of Beirut Medical Center Beirut Lebanon
Department of Neurology and Epileptology University of Aachen Aachen 52074 Germany
Department of Neurology Antwerp University Hospital Edegem 2650 Belgium
Department of Neurology Baylor College of Medicine
Department of Neurology Beaumont Hospital Dublin D09 FT51 Ireland
Department of Neurology CUB Erasme Hospital Hôpital Universitaire de Bruxelles 1070 Brussels Belgium
Department of Neurology Hofstra Northwell Medical School New York NY USA
Department of Neurology Hôpital Pellegrin Bordeaux France
Department of Neurology Icahn School of Medicine at Mount Sinai New York NY 10029 USA
Department of Neurology Istanbul Faculty of Medicine Istanbul University Istanbul Turkey
Department of Neurology Kaohsiung Chang Gung Memorial Hospital Kaohsiung Taiwan
Department of Neurology Ludwig Maximilians University Munich Germany
Department of Neurology Massachusetts General Hospital and Harvard Medical School Boston MA USA
Department of Neurology Medical University of Vienna Vienna 1090 Austria
Department of Neurology Morriston Hospital Swansea Bay University Bay Health Board Swansea Wales UK
Department of Neurology Neurological Institute Cleveland Clinic Cleveland OH 44195 USA
Department of Neurology New York University Langone Health New York NY USA
Department of Neurology Sheba Medical Center Ramat Gan Israel
Department of Neurology Thomas Jefferson University Hospital Philadelphia PA 19107 USA
Department of Neurology University Hospital of Strasbourg Strasbourg France
Department of Neurology University of California San Francisco CA 94143 USA
Department of Neurology University of Sao Paulo School of Medicine Brazil
Department of Neurology University of Ulm Ulm 89081 Germany
Department of Neurology Vanderbilt University Medical Center Nashville TN USA
Department of Neuropediatrics Children's Hospital Goethe University Frankfurt Frankfurt Germany
Department of Neurosciences Université de Montréal Montréal CA 26758 Canada
Department of Paediatrics and Child Health University of Otago Wellington New Zealand
Department of Pediatric Neurology Chang Gung Memorial Hospital Taoyuan Taiwan
Department of Pediatric Neurology Vivantes Hospital Neukölln 12351 Berlin Germany
Department of Pediatric Neuroscience Fondazione IRCCS Istituto Neurologico Carlo Besta Milan Italy
Department of Pediatrics and Neonatology Medical University of Vienna Vienna 1090 Austria
Department of Pediatrics and Neurology Nationwide Children's Hospital Columbus OH USA
Department of Pediatrics Filderklinik Filderstadt Germany
Department of Pediatrics Fukuoka Sanno Hospital Japan
Department of Pediatrics Nationwide Children's Hospital Columbia Ohio USA
Department of Pharmacology and Pharmacy The University of Hong Kong Pokfulam Hong Kong
Department of Pharmacology and Therapeutics University of Liverpool Liverpool L69 3GL UK
Department of Psychiatry and Behavioral Sciences SUNY Downstate Medical Center Brooklyn NY USA
Department of Psychiatry Harvard Medical School Boston MA USA
Department of Psychiatry Icahn School of Medicine at Mount Sinai New York NY 10029 USA
Department of Psychiatry Psychosomatic Medicine and Psychotherapy University Hospital Frankfurt
Department of Psychiatry Psychotherapy and Psychosomatics University Hospital Würzburg
Department of Psychiatry The University of Hong Kong Pokulam Hong Kong
Department of Psychiatry University of Cape Town South Africa
Department of Psychiatry University of Oxford Oxford UK
Department of Public Health Pwani University Kilifi Kenya
Division of Brain Sciences Imperial College London London SW7 2AZ UK
Division of Neurology Ann and Robert H Lurie Children's Hospital of Chicago Chicago IL USA
Division of Psychiatry Centre for Clinical Brain Sciences University of Edinburgh Edinburgh UK
Division of Psychiatry University College London
Epilepsy Center Hessen Marburg Department of Neurology Philipps University Marburg Marburg Germany
Epilepsy Center Kleinwachau Radeberg 01454 Germany
Epilepsy Center Kork Kehl Kork 77694 Germany
Epilepsy Clinic Hospital Sirio Libanes Sao Paulo Brazil
Epilepsy Research Centre University of Melbourne Austin Health Heidelberg 3084 Australia
Florey and Murdoch Children's Research Institutes Parkville Victoria 3052 Australia
Folkhälsan Research Center Helsinki 00290 Finland
General Medical Research Center School of Medicine Fukuoka University Japan
Genomic Medicine Institute Lerner Research Institute Cleveland Clinic Cleveland OH 44195 USA
Hasso Plattner Institute Digital Engineering Faculty University of Potsdam Germany
Helsinki University Hospital Helsinki Finland
Hereditary Research Lab Bethlehem University Bethlehem Palestine
Hotchkiss Brain Institute Cumming School of Medicine University of Calgary Calgary Alberta Canada
Human Genetics Training Program Vanderbilt University Nashville TN USA
IMT School for Advanced Studies Lucca Lucca Italy
Institute for Genomic Medicine Columbia University Medical Center New York NY 10032 USA
Institute for Molecular Medicine Finland FIMM HiLIFE University of Helsinki Helsinki Finland
Institute for Molecular Medicine Finland University of Helsinki Helsinki 0014 Finland
Institute of Biomedical Sciences Faculty of Medicine Vilnius University Vilnius Lithuania
Institute of Clinical Medicine University of Eastern Finland Kuopio 70210 Finland
Institute of Clinical Molecular Biology Christian Albrechts University of Kiel Kiel Germany
Institute of Human Genetics Bern University Hospital Bern Switzerland
Institute of Human Genetics University of Leipzig Medical Center Leipzig Germany
Integrated Diagnostics for Epilepsy Fondazione IRCCS Istituto Neurologico C Besta Milan Italy
IRCCS Azienda Ospedaliero Universitaria di Bologna Medical Genetics Unit Bologna Italy
IRCCS Istituto delle Scienze Neurologiche di Bologna Bologna Italy
IRCCS Istituto Giannina Gaslini Genova Italy
Istanbul University Cerrahpaşa Cerrahpaşa Medical Faculty Department of Neurology Istanbul Turkey
Kintampo Health Research Centre Ghana Health Service Kintampo Ghana
Kuopio Epilepsy Center Neurocenter Kuopio University Hospital Kuopio 70210 Finland
Laboratory for Neurogenetics RIKEN Center for Brain Science Wako Saitama Japan
LOEWE Center for Personalized Translational Epilepsy Research Goethe University Frankfurt Germany
Lyon's Neuroscience Research Center INSERM U1028 CNRS UMR 5292 Lyon France
Medical School Nova Southeastern University Fort Lauderdale FL USA
Medicum University of Helsinki Helsinki 00290 Finland
Mendelics Genomic Analysis São Paulo Brazil
MRC Integrative Epidemiology Unit at University of Bristol Bristol BS8 2BN UK
National Epilepsy Center Shizuoka Institute of Epilepsy and Neurological Disorder Shizuoka Japan
Neurology Department Aneurin Bevan University Health Board Newport Wales UK
Neurology Department St James's Hospital Dublin D03 VX82 Ireland
Neurology Department University Hospital of Nancy UMR 7039 CNRS Lorraine University Nancy France
Neurology Massachusetts General Hospital Boston MA USA
Neurology Northwestern University Chicago IL USA
Neurophysiology Fondazione IRCCS Istituto Neurologico Carlo Besta Milan Italy
Neurophysiopatology and Movement Disorders Clinic University of Messina Messina Italy
Neuropsychiatry Laboratory IRCCS Santa Lucia Foundation Rome Italy
Neuroscience Department Meyer Children's Hospital IRCCS Florence Italy
Neuroscience Unit KEMRI Wellcome Trust Research Programme Kilifi Kenya
O'Brien Institute for Public Health University of Calgary Calgary Alberta Canada
Pediatric Neurology University of Giessen Germany
Pediatric Research Center University of Helsinki Helsinki Finland
Perelman School of Medicine University of Pennsylvania Philadelphia PA USA
Population Health Sciences Bristol Medical School University of Bristol Bristol BS8 2BN UK
Private Neurological Practice Stuttgart Germany
Program in Medical and Population Genetics Broad Institute of MIT and Harvard Cambridge MA USA
Research Institute Rehabilitation Transition Palliation PMU Salzburg Austria
School of Life Sciences University of Glasgow Glasgow G12 8QQ UK
School of Pharmacy and Biomolecular Sciences The Royal College of Surgeons in Ireland Dublin Ireland
Sheppard Pratt 6501 North Charles Street Baltimore Maryland USA
St George's University Hospital NHS Foundation Trust London UK
Stanford University Palo Alto CA USA
Stanley Center for Psychiatric Research Broad Institute of MIT and Harvard Cambridge MA USA
Stanley Division of Developmental Neurovirology Johns Hopkins University Baltimore Maryland USA
Swansea University Medical School Swansea University Swansea Wales UK
Tel Aviv University Sackler Faculty of Medicine Ramat Aviv 69978 Israel
The Emmes Company Rockville MD USA
The FutureNeuro Research Centre Dublin Ireland
Translational and Clinical Research Institute Newcastle University Newcastle Upon Tyne UK
University Health Network University of Toronto Toronto ON Canada
University of Health and Allied Science in Ho Ghana
University of Pittsburgh Pittsburgh PA USA
Vanderbilt Genetics Institute Vanderbilt University Medical Center Nashville TN USA
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