Polygenic risk score analysis reveals shared genetic burden between epilepsy and psychiatric comorbidities
Abstract
Abstract Background One in three people with epilepsy experiences psychiatric comorbidity, with higher rates in people with drug-resistant epilepsy. Despite their high heritabilities, finding genetic links between epilepsy and psychiatric disorders has proven difficult. We used polygenic risk scoring (PRS) to test whether people with epilepsy have an increased polygenic burden of common genetic variants for depression, anxiety, psychosis, and attention deficit/hyperactivity disorder (ADHD), and examined whether such polygenic burden influences the response to pharmacological treatment of epilepsy. Methods Phenotype data in the UK Biobank were assessed to identify people with 1) epilepsy (n=8 488), 2) depression (n=143 440), 3) psychosis (n=2 357), 4) ADHD (n=89), and 5) anxiety (n=18 222. Using genotype data and restricting to Caucasian-ancestry samples (n=409 634), PRS for each psychiatric trait were calculated and multinomial regression was used to compare 1) population controls, 2) people with epilepsy and no psychiatric illness, 3) people with epilepsy and the psychiatric trait of interest, and 4) people with the psychiatric trait of interest and no epilepsy. Fixed-effect meta-analysis was used to compare psychiatric PRS in drug-resistant and drug-responsive epilepsy samples from the UK Biobank (n=1 640) and the EpiPGX consortium (n=3 449). Results After correction for multiple testing, people with epilepsy showed elevated PRS for depression (p<2 x10 −16 ), psychosis (p=0.04) and ADHD (p<0.001). Patients with drug-resistant epilepsy had an increased PRS for psychosis (p=0.002) and depression (p=0.0004) relative to responsive cases. Conclusion We present evidence that the common genetic basis of epilepsy overlaps with that of psychiatric conditions which are frequently comorbid in people with epilepsy. Common genetic variants that drive psychiatric illness are enriched in people with drug-resistant epilepsy. These results further our understanding of the genetic architecture of epilepsy and suggest a potential future role for polygenic interpretation of common variants in prognostic stratification, both for seizure-treatment outcomes and non-seizure comorbidities.
Authors 22
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Royal College of Surgeons in Ireland
Affiliation as printed
School of Pharmacy and Biomolecular Sciences
The SFI FutureNeuro Research Centre
School of Pharmacy and Biomolecular Sciences, RCSI Dublin, Ireland
The SFI FutureNeuro Research Centre, RCSI Dublin, Ireland
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Newcastle upon Tyne Hospitals NHS Foundation Trust · Newcastle University
Affiliation as printed
Department of Clinical Neurosciences, Newcastle Upon Tyne Hospitals NHS Foundation Trust
Translational and Clinical Research Institute, Newcastle University
Department of Clinical Neurosciences, Newcastle Upon Tyne Hospitals NHS Foundation Trust, United Kingdom
Translational and Clinical Research Institute, Newcastle University, United Kingdom
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Broad Institute · Cleveland Clinic · Stanley Center for Psychiatric Research · UCL Queen Square Institute of Neurology · University College London
Affiliation as printed
Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic
Stanley Center for Psychiatric Research, Broad Institute of Harvard and M.I.T
UCL Queen Square Institute of Neurology, London WC1N 3BG and Chalfont Centre for Epilepsy
Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, United States of America
Stanley Center for Psychiatric Research, Broad Institute of Harvard and M.I.T, Cambridge, MA, United States of America
UCL Queen Square Institute of Neurology, London WC1N 3BG and Chalfont Centre for Epilepsy, Bucks, United Kingdom
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Hertie Institute for Clinical Brain Research · University of Tübingen · RWTH Aachen University
Affiliation as printed
Department of Epileptology and Neurology, University of Aachen
Department of Neurology & Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen
Department of Epileptology and Neurology, University of Aachen, Aachen, Germany
Department of Neurology & Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany
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University of Luxembourg · Luxembourg Centre for Systems Biomedicine
Affiliation as printed
Luxembourg Centre for Systems Biomedicine, University of Luxembourg
Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Luxembourg
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The Alfred Hospital · Alfred Health · Monash University
Affiliation as printed
Department of Neuroscience, The Central Clinical School, Alfred Health, Monash University
Department of Neuroscience, The Central Clinical School, Alfred Health, Monash University, Melbourne, Australia
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Affiliation as printed
Department of Molecular & Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool
Department of Molecular & Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom
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Istituto Giannina Gaslini · University of Genoa
Affiliation as printed
Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genova
IRCCS ‘G. Gaslini’ Institute
Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genova, Genova, Italy
IRCCS 'G. Gaslini' Institute, Genova, Italy
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University Medical Center Utrecht
Affiliation as printed
Department of Genetics, University Medical Center Utrecht
Department of Genetics, University Medical Center Utrecht, Utrecht, The Netherlands
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Université Libre de Bruxelles · Erasmus Hospital
Affiliation as printed
Department of Neurology, Hôpital Erasme, Université Libre de Bruxelles
Department of Neurology, Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium
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Affiliation as printed
Department of Molecular & Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool
Department of Molecular & Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom
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Affiliation as printed
CNS department, deCODE genetics
CNS department, deCODE genetics, Reykjavík, Iceland
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Affiliation as printed
CNS department, deCODE genetics
CNS department, deCODE genetics, Reykjavík, Iceland
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Belfast Health and Social Care Trust
Affiliation as printed
Department of Neurosciences Belfast Health and Social Care Trust Belfast UK
Department of Neurosciences Belfast Health and Social Care Trust Belfast UK, United Kingdom
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Affiliation as printed
Department of Brain Sciences, Faculty of Medicine, Imperial College London
Department of Brain Sciences, Faculty of Medicine, Imperial College London, United Kingdom
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University of Liverpool · The Alfred Hospital · Alfred Health · Monash University
Affiliation as printed
Department of Molecular & Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool
Department of Neuroscience, The Central Clinical School, Alfred Health, Monash University
Department of Molecular & Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom
Department of Neuroscience, The Central Clinical School, Alfred Health, Monash University, Melbourne, Australia
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Affiliation as printed
Department of Health Data Science, University of Liverpool
Department of Health Data Science, University of Liverpool, Liverpool, United Kingdom
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Hertie Institute for Clinical Brain Research · University of Tübingen
Affiliation as printed
Department of Neurology & Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen
Department of Neurology & Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany
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Royal College of Surgeons in Ireland · Beaumont Hospital · Botsford Hospital · Beaumont Hospital, Dearborn
Affiliation as printed
Department of Neurology, Beaumont Hospital
The SFI FutureNeuro Research Centre
Department of Neurology, Beaumont Hospital, Dublin, Ireland
The SFI FutureNeuro Research Centre, RCSI Dublin, Ireland
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UCL Queen Square Institute of Neurology · University College London
Affiliation as printed
UCL Queen Square Institute of Neurology, London WC1N 3BG and Chalfont Centre for Epilepsy
UCL Queen Square Institute of Neurology, London WC1N 3BG and Chalfont Centre for Epilepsy, Bucks, United Kingdom
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Newcastle upon Tyne Hospitals NHS Foundation Trust · Newcastle University
Affiliation as printed
Department of Clinical Neurosciences, Newcastle Upon Tyne Hospitals NHS Foundation Trust
Translational and Clinical Research Institute, Newcastle University
Department of Clinical Neurosciences, Newcastle Upon Tyne Hospitals NHS Foundation Trust, United Kingdom
Translational and Clinical Research Institute, Newcastle University, United Kingdom
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Gianpiero L. Cavalleri corresponding
Royal College of Surgeons in Ireland
Affiliation as printed
School of Pharmacy and Biomolecular Sciences
The SFI FutureNeuro Research Centre
School of Pharmacy and Biomolecular Sciences, RCSI Dublin, Ireland
The SFI FutureNeuro Research Centre, RCSI Dublin, Ireland
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