Human-lineage-specific genomic elements are associated with neurodegenerative disease and APOE transcript usage
Nature Communications, vol. 12, pp. 2076
Abstract
Knowledge of genomic features specific to the human lineage may provide insights into brain-related diseases. We leverage high-depth whole genome sequencing data to generate a combined annotation identifying regions simultaneously depleted for genetic variation (constrained regions) and poorly conserved across primates. We propose that these constrained, non-conserved regions (CNCRs) have been subject to human-specific purifying selection and are enriched for brain-specific elements. We find that CNCRs are depleted from protein-coding genes but enriched within lncRNAs. We demonstrate that per-SNP heritability of a range of brain-relevant phenotypes are enriched within CNCRs. We find that genes implicated in neurological diseases have high CNCR density, including APOE, highlighting an unannotated intron-3 retention event. Using human brain RNA-sequencing data, we show the intron-3-retaining transcript to be more abundant in Alzheimer's disease with more severe tau and amyloid pathological burden. Thus, we demonstrate potential association of human-lineage-specific sequences in brain development and neurological disease.
Authors 99
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NIHR Great Ormond Street Hospital Biomedical Research Centre · UCL Queen Square Institute of Neurology · University College London
Affiliation as printed
Department of Genetics and Genomic Medicine, Great Ormond Street Institute of Child Health, University College London, London, UK
Department of Neurodegenerative Disease, Queen Square Institute of Neurology, University College London (UCL), London, UK
NIHR Great Ormond Street Hospital Biomedical Research Centre, University College London, London, UK
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NIHR Great Ormond Street Hospital Biomedical Research Centre · UCL Queen Square Institute of Neurology · University College London
Affiliation as printed
Department of Genetics and Genomic Medicine, Great Ormond Street Institute of Child Health, University College London, London, UK
Department of Neurodegenerative Disease, Queen Square Institute of Neurology, University College London (UCL), London, UK
NIHR Great Ormond Street Hospital Biomedical Research Centre, University College London, London, UK
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NIHR Great Ormond Street Hospital Biomedical Research Centre · UCL Queen Square Institute of Neurology · University College London
Affiliation as printed
Department of Genetics and Genomic Medicine, Great Ormond Street Institute of Child Health, University College London, London, UK
Department of Neurodegenerative Disease, Queen Square Institute of Neurology, University College London (UCL), London, UK
NIHR Great Ormond Street Hospital Biomedical Research Centre, University College London, London, UK
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NIHR Great Ormond Street Hospital Biomedical Research Centre · UCL Queen Square Institute of Neurology · University College London
Affiliation as printed
Department of Genetics and Genomic Medicine, Great Ormond Street Institute of Child Health, University College London, London, UK
Department of Neurodegenerative Disease, Queen Square Institute of Neurology, University College London (UCL), London, UK
NIHR Great Ormond Street Hospital Biomedical Research Centre, University College London, London, UK
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NIHR Great Ormond Street Hospital Biomedical Research Centre · UCL Queen Square Institute of Neurology · University College London
Affiliation as printed
Department of Genetics and Genomic Medicine, Great Ormond Street Institute of Child Health, University College London, London, UK
Department of Neurodegenerative Disease, Queen Square Institute of Neurology, University College London (UCL), London, UK
NIHR Great Ormond Street Hospital Biomedical Research Centre, University College London, London, UK
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NIHR Great Ormond Street Hospital Biomedical Research Centre · UCL Queen Square Institute of Neurology · University College London
Affiliation as printed
Department of Genetics and Genomic Medicine, Great Ormond Street Institute of Child Health, University College London, London, UK
Department of Neurodegenerative Disease, Queen Square Institute of Neurology, University College London (UCL), London, UK
NIHR Great Ormond Street Hospital Biomedical Research Centre, University College London, London, UK
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NIHR Great Ormond Street Hospital Biomedical Research Centre · UCL Queen Square Institute of Neurology · University College London
Affiliation as printed
Department of Genetics and Genomic Medicine, Great Ormond Street Institute of Child Health, University College London, London, UK
Department of Neurodegenerative Disease, Queen Square Institute of Neurology, University College London (UCL), London, UK
NIHR Great Ormond Street Hospital Biomedical Research Centre, University College London, London, UK
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UCL Queen Square Institute of Neurology · University College London
Affiliation as printed
Department of Neurodegenerative Disease, Queen Square Institute of Neurology, University College London (UCL), London, UK
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University of London · Queen Mary University of London · UCL Queen Square Institute of Neurology · University College London
Affiliation as printed
Department of Molecular Neuroscience, Queen Square Institute of Neurology, University College London (UCL), London, UK
Preventive Neurology Unit, Wolfson Institute of Preventive Medicine, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
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UCL Queen Square Institute of Neurology · University College London
Affiliation as printed
Department of Molecular Neuroscience, Queen Square Institute of Neurology, University College London (UCL), London, UK
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Affiliation as printed
Institute of Translational Medicine, University of Liverpool, Liverpool, UK
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UCL Queen Square Institute of Neurology · University College London
Affiliation as printed
Department of Molecular Neuroscience, Queen Square Institute of Neurology, University College London (UCL), London, UK
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UCL Queen Square Institute of Neurology · University College London
Affiliation as printed
Department of Clinical and Movement Neuroscience, Queen Square Institute of Neurology, University College London (UCL), London, UK
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UCL Queen Square Institute of Neurology · University College London
Affiliation as printed
Department of Clinical and Movement Neuroscience, Queen Square Institute of Neurology, University College London (UCL), London, UK
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UCL Queen Square Institute of Neurology · University College London
Affiliation as printed
Department of Molecular Neuroscience, Queen Square Institute of Neurology, University College London (UCL), London, UK
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Cardiff University · Medical Research Council
Affiliation as printed
Biostatistics & Bioinformatics Unit, Institute of Psychological Medicine and Clinical Neuroscience, MRC Centre for Neuropsychiatric Genetics & Genomics, Cardiff, UK
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King Faisal Specialist Hospital & Research Centre · UCL Queen Square Institute of Neurology · University College London
Affiliation as printed
Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
Department of Molecular Neuroscience, Queen Square Institute of Neurology, University College London (UCL), London, UK
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UCL Queen Square Institute of Neurology · University College London
Affiliation as printed
Department of Genetics and Genomic Medicine, Great Ormond Street Institute of Child Health, University College London, London, UK
Department of Molecular Neuroscience, Queen Square Institute of Neurology, University College London (UCL), London, UK
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Affiliation as printed
Institute of Translational Medicine, University of Liverpool, Liverpool, UK
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UCL Queen Square Institute of Neurology · University College London
Affiliation as printed
Department of Molecular Neuroscience, Queen Square Institute of Neurology, University College London (UCL), London, UK
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Affiliation as printed
Institute of Healthy Ageing, University College London (UCL), London, UK
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Affiliation as printed
Institute of Translational Medicine, University of Liverpool, Liverpool, UK
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UCL Queen Square Institute of Neurology · University College London
Affiliation as printed
Department of Molecular Neuroscience, Queen Square Institute of Neurology, University College London (UCL), London, UK
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Affiliation as printed
University of Reading, Reading, UK
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UCL Queen Square Institute of Neurology · University College London
Affiliation as printed
Department of Molecular Neuroscience, Queen Square Institute of Neurology, University College London (UCL), London, UK
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UK Dementia Research Institute · UCL Queen Square Institute of Neurology · University College London
Affiliation as printed
Department of Molecular Neuroscience, Queen Square Institute of Neurology, University College London (UCL), London, UK
UK Dementia Research Institute, University College London (UCL), London, UK
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Affiliation as printed
Institute of Cardiovascular Science, University College London (UCL), London, UK
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UCL Queen Square Institute of Neurology · University College London
Affiliation as printed
Department of Molecular Neuroscience, Queen Square Institute of Neurology, University College London (UCL), London, UK
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Affiliation as printed
University of Reading, Reading, UK
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UCL Queen Square Institute of Neurology · University College London
Affiliation as printed
Department of Molecular Neuroscience, Queen Square Institute of Neurology, University College London (UCL), London, UK
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UCL Queen Square Institute of Neurology · University College London
Affiliation as printed
Department of Neurodegenerative Disease, Queen Square Institute of Neurology, University College London (UCL), London, UK
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Affiliation as printed
MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University School of Medicine, Cardiff, UK
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UCL Queen Square Institute of Neurology · University College London
Affiliation as printed
Department of Molecular Neuroscience, Queen Square Institute of Neurology, University College London (UCL), London, UK
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UCL Queen Square Institute of Neurology · University College London
Affiliation as printed
Department of Clinical and Movement Neuroscience, Queen Square Institute of Neurology, University College London (UCL), London, UK
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Affiliation as printed
MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University School of Medicine, Cardiff, UK
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Centre National de la Recherche Scientifique · Inserm · Sorbonne Université · Pitié-Salpêtrière Hospital · Institut du Cerveau · Université Pierre-et-Marie-Curie
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Institut du Cerveau et de la Moelle épinière, ICM, Inserm U 1127, CNRS, UMR 7225, Sorbonne Universités, UPMC University Paris 06, UMR S 1127, AP-HP, Pitié-Salpêtrière Hospital, Paris, France
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Centre National de la Recherche Scientifique · Inserm · Sorbonne Université · Pitié-Salpêtrière Hospital · Institut du Cerveau · Université Pierre-et-Marie-Curie
Affiliation as printed
Institut du Cerveau et de la Moelle épinière, ICM, Inserm U 1127, CNRS, UMR 7225, Sorbonne Universités, UPMC University Paris 06, UMR S 1127, AP-HP, Pitié-Salpêtrière Hospital, Paris, France
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Centre National de la Recherche Scientifique · Inserm · Sorbonne Université · Pitié-Salpêtrière Hospital · Institut du Cerveau · Université Pierre-et-Marie-Curie
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Institut du Cerveau et de la Moelle épinière, ICM, Inserm U 1127, CNRS, UMR 7225, Sorbonne Universités, UPMC University Paris 06, UMR S 1127, AP-HP, Pitié-Salpêtrière Hospital, Paris, France
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Centre National de la Recherche Scientifique · Inserm · Sorbonne Université · Pitié-Salpêtrière Hospital · Institut du Cerveau · Université Pierre-et-Marie-Curie · CIC Pitié Neurosciences
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Institut du Cerveau et de la Moelle épinière, ICM, Inserm U 1127, CNRS, UMR 7225, Sorbonne Universités, UPMC University Paris 06, UMR S 1127, Centre d’Investigation Clinique Pitié Neurosciences CIC-1422, AP-HP, Pitié-Salpêtrière Hospital, Paris, France
Institut du Cerveau et de la Moelle épinière, ICM, Inserm U 1127, CNRS, UMR 7225, Sorbonne Universités, UPMC University Paris 06, UMR S 1127, Centre d'Investigation Clinique Pitié Neurosciences CIC-1422, AP-HP, Pitié-Salpêtrière Hospital, Paris, France
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Université Toulouse III - Paul Sabatier · Inserm
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INSERM UMR 1220 and Paul Sabatier University, Toulouse, France
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German Center for Neurodegenerative Diseases · Hertie Institute for Clinical Brain Research · University of Tübingen
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Department for Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, German Center for Neurodegenerative Diseases, DZNE, German Center for Neurodegenerative Diseases, University of Tübingen, Tübingen, Germany
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German Center for Neurodegenerative Diseases · Hertie Institute for Clinical Brain Research · University of Tübingen
Affiliation as printed
Department for Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, German Center for Neurodegenerative Diseases, DZNE, German Center for Neurodegenerative Diseases, University of Tübingen, Tübingen, Germany
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German Center for Neurodegenerative Diseases · Hertie Institute for Clinical Brain Research · University of Tübingen
Affiliation as printed
Department for Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, German Center for Neurodegenerative Diseases, DZNE, German Center for Neurodegenerative Diseases, University of Tübingen, Tübingen, Germany
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German Center for Neurodegenerative Diseases · Hertie Institute for Clinical Brain Research · University of Tübingen
Affiliation as printed
Department for Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, German Center for Neurodegenerative Diseases, DZNE, German Center for Neurodegenerative Diseases, University of Tübingen, Tübingen, Germany
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German Center for Neurodegenerative Diseases · Hertie Institute for Clinical Brain Research · University of Tübingen
Affiliation as printed
Department for Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, German Center for Neurodegenerative Diseases, DZNE, German Center for Neurodegenerative Diseases, University of Tübingen, Tübingen, Germany
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Affiliation as printed
Centre for Genetic Epidemiology, Institute for Clinical Epidemiology and Applied Biometry, University of Tubingen, Tübingen, Germany
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German Center for Neurodegenerative Diseases · Hertie Institute for Clinical Brain Research · University of Tübingen
Affiliation as printed
Department for Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, German Center for Neurodegenerative Diseases, DZNE, German Center for Neurodegenerative Diseases, University of Tübingen, Tübingen, Germany
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National Institutes of Health · National Institute on Aging
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Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD, USA
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National Institutes of Health · National Institute on Aging
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Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD, USA
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National Institutes of Health · National Institute on Aging
Affiliation as printed
Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD, USA
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National Institutes of Health · National Institute of Neurological Disorders and Stroke · National Institute on Aging
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Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD, USA
National Institute of Neurological Disorders and Stroke, Bethesda, MD, USA
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University of Southern California
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Department of Translational Genomics, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
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National Institutes of Health · University of Illinois Urbana-Champaign · National Institute on Aging
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Department of Computer Science, University of Illinois at Urbana-Champaign, Urbana, IL, USA
Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD, USA
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National Institutes of Health · National Institute on Aging
Affiliation as printed
Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD, USA
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National Institutes of Health · National Institute on Aging
Affiliation as printed
Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD, USA
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Translational Genomics Research Institute
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Neurogenomics Division, TGen, Phoenix, AZ, USA
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Baylor College of Medicine · Texas Children's Hospital
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Departments of Neurology, Neuroscience, and Molecular & Human Genetics, Baylor College of Medicine, Houston, TX, USA
Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital, Houston, TX, USA
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National Institutes of Health · National Institute on Aging
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Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD, USA
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National Institutes of Health · Data Tecnica International (United States) · National Institute on Aging
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Data Tecnica International, Glen Echo, MD, USA
Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD, USA
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Baylor College of Medicine · Texas Children's Hospital
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Departments of Neurology, Neuroscience, and Molecular & Human Genetics, Baylor College of Medicine, Houston, TX, USA
Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital, Houston, TX, USA
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Affiliation as printed
Ken and Ruth Davee Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
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Gladstone Institutes · University of California, San Francisco · Taube Koret Center
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Department of Neurology and Physiology, University of California, San Francisco, CA, USA
Gladstone Institute of Neurological Disease, San Francisco, CA, USA
Taube/Koret Center for Neurodegenerative Disease Research, San Francisco, CA, USA
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Affiliation as printed
Northwestern University Feinberg School of Medicine, Chicago, IL, USA
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National Institutes of Health · National Institute of Neurological Disorders and Stroke
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National Institutes of Health Division of Clinical Research, NINDS, National Institutes of Health, Bethesda, MD, USA
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National Institutes of Health · National Institute on Aging
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Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD, USA
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National Institute of Neurological Disorders and Stroke
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Neurodegenerative Diseases Research Unit, National Institute of Neurological Disorders and Stroke, Bethesda, MD, USA
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National Institutes of Health · National Institute on Aging
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Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD, USA
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Columbia University Irving Medical Center · Columbia University
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Department of Neurology, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY, USA
Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY, USA
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Montreal Neurological Institute and Hospital · McGill University
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Montreal Neurological Institute and Hospital, Department of Neurology & Neurosurgery, Department of Human Genetics, McGill University, Montréal, QC, Canada
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Montreal Neurological Institute and Hospital · McGill University
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Montreal Neurological Institute and Hospital, Department of Neurology & Neurosurgery, Department of Human Genetics, McGill University, Montréal, QC, Canada
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Montreal Neurological Institute and Hospital · McGill University
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Montreal Neurological Institute and Hospital, Department of Neurology & Neurosurgery, Department of Human Genetics, McGill University, Montréal, QC, Canada
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Leiden University Medical Center
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Department of Neurology, Leiden University Medical Center, Leiden, The Netherlands
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Leiden University Medical Center
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Department of Neurology, Leiden University Medical Center, Leiden, The Netherlands
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Instituto de Biomedicina de Sevilla · Hospital Universitario Virgen del Rocío · Universidad de Sevilla
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Instituto de Biomedicina de Sevilla Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville, Spain
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University Hospital Mútua de Terrassa
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Fundació Docència I Recerca Mútua de Terrassa and Movement Disorders Unit, Department of Neurology, University Hospital Mutua de Terrassa, Terrassa, Barcelona, Spain
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University Hospital Mútua de Terrassa
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Fundació Docència I Recerca Mútua de Terrassa and Movement Disorders Unit, Department of Neurology, University Hospital Mutua de Terrassa, Terrassa, Barcelona, Spain
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Hospital Universitario Central de Asturias
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Hospital Universitario Central de Asturias, Oviedo, Spain
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Affiliation as printed
Hospital Universitario San Cecilio de Granada, Universidad de Granada, Granada, Spain
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Biogipuzkoa Health Research Institute
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Instituto de Investigación Sanitaria Biodonostia, San Sebastián, Spain
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Affiliation as printed
Hospital Clinic de Barcelona, Barcelona, Spain
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Hospital Universitario Central de Asturias
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Hospital Universitario Central de Asturias, Oviedo, Spain
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Affiliation as printed
Hospital Clinic de Barcelona, Barcelona, Spain
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UCL Queen Square Institute of Neurology · University College London · Universidad de Murcia
Affiliation as printed
Departamento de Ingeniería de la Información y las Comunicaciones, Universidad de Murcia, Murcia, Spain
Department of Neurodegenerative Disease, Queen Square Institute of Neurology, University College London (UCL), London, UK
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University Hospital Mútua de Terrassa
Affiliation as printed
Fundació Docència I Recerca Mútua de Terrassa and Movement Disorders Unit, Department of Neurology, University Hospital Mutua de Terrassa, Terrassa, Barcelona, Spain
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Instituto de Biomedicina de Sevilla · Hospital Universitario Virgen del Rocío · Universidad de Sevilla
Affiliation as printed
Instituto de Biomedicina de Sevilla Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville, Spain
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Instituto de Biomedicina de Sevilla · Hospital Universitario Virgen del Rocío · Universidad de Sevilla
Affiliation as printed
Instituto de Biomedicina de Sevilla Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville, Spain
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Instituto de Biomedicina de Sevilla · Hospital Universitario Virgen del Rocío · Universidad de Sevilla
Affiliation as printed
Instituto de Biomedicina de Sevilla Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville, Spain
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Affiliation as printed
Hospital General de Segovia, Segovia, Spain
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Universitat Autònoma de Barcelona · Hospital de Sant Pau · Biomedical Research Networking Center on Neurodegenerative Diseases · Centro de Investigación Biomédica en Red
Affiliation as printed
Centro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas, Madrid, Spain
Memory Unit, Department of Neurology, IIB Sant Pau, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain
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Affiliation as printed
Hospital Clinic de Barcelona, Barcelona, Spain
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University Hospital Mútua de Terrassa
Affiliation as printed
Fundació Docència I Recerca Mútua de Terrassa and Movement Disorders Unit, Department of Neurology, University Hospital Mutua de Terrassa, Terrassa, Barcelona, Spain
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Universitat Autònoma de Barcelona · Hospital de Sant Pau · Biomedical Research Networking Center on Neurodegenerative Diseases · Centro de Investigación Biomédica en Red
Affiliation as printed
Centro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas, Madrid, Spain
Memory Unit, Department of Neurology, IIB Sant Pau, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain
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Affiliation as printed
Hospital General de Segovia, Segovia, Spain
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Affiliation as printed
Centro de Investigacion Biomedica, Universidad de Granada, Granada, Spain
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Instituto de Investigación Biosanitaria de Granada · Hospital Universitario Virgen de las Nieves
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Hospital Universitario Virgen de las Nieves, Instituto de Investigación Biosanitaria de Granada, Granada, Spain
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Affiliation as printed
Hospital Clinic de Barcelona, Barcelona, Spain
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Hospital Universitario Fundación Jiménez Díaz · Instituto de Investigación Sanitaria Fundación Jiménez Díaz
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Hospital Universitario Marqués de Valdecilla-IDIVALS, Instituto de Investigación Sanitaria Fundación Jiménez Díaz, Madrid, Spain
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Affiliation as printed
Hospital Clinic de Barcelona, Barcelona, Spain
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Affiliation as printed
Hospital Clinic de Barcelona, Barcelona, Spain
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