Genetic variation across RNA metabolism and cell death gene networks is implicated in the semantic variant of primary progressive aphasia
Bonham, Luke W. (University of California, San Francisco (UCSF))
Steele, Natasha Z. R. (University of California, San Francisco (UCSF))
Karch, Celeste M. (Department of Psychiatry. Washington University)
Broce, Iris (University of California, San Francisco (UCSF))
Geier, Ethan G. (University of California, San Francisco (UCSF))
Wen, Natalie L. (Department of Psychiatry. Washington University)
Momeni, Parastoo (Texas Tech University Health Science Center. Laboratory of Neurogenetics)
Hardy, John (UCL Institute of Neurology (Regne Unit). Department of Molecular Neuroscience)
Miller, Zachary A. (University of California, San Francisco (UCSF))
Gorno-Tempini, Maria Luisa (University of California, San Francisco (UCSF))
Hess, Christopher P. (University of California, San Francisco (UCSF))
Lewis, Patrick (School of Pharmacy. University of Reading. Whiteknights)
Miller, Bruce L. (University of California, San Francisco (UCSF))
Seeley, William W. (University of California, San Francisco (UCSF))
Manzoni, Claudia (School of Pharmacy. University of Reading. Whiteknights)
Desikan, Rahul S. (University of California, San Francisco (UCSF))
Baranzini, Sergio E. (University of California, San Francisco (UCSF))
Ferrari, Raffaele (UCL Institute of Neurology (Regne Unit). Department of Molecular Neuroscience)
Yokoyama, Jennifer S. (University of California, San Francisco (UCSF))
Hernandez, D. G. (UCL Institute of Neurology (Regne Unit))
Nalls, M. A. (National Institute on Aging (Bethesda, Estats Units d'Amèrica))
Rohrer, J. D. (Dementia Research Centre. Department of Neurodegenerative Disease. UCL Institute of Neurology)
Ramasamy, Adaikalavan (The Jenner Institute. University of Oxford)
Kwok, J. B. J. (School of Medical Sciences. University of New South Wales)
Dobson-Stone, Carol (School of Medical Sciences. University of New South Wales)
Schofield, P. R. (School of Medical Sciences. University of New South Wales)
Halliday, G. M. (School of Medical Sciences. University of New South Wales)
Hodges, J. R. (School of Medical Sciences. University of New South Wales)
Piguet, O. (School of Medical Sciences. University of New South Wales)
Bartley, Lauren (School of Medical Sciences. University of New South Wales)
Thompson, E. (Department of Paediatrics. University of Adelaide)
Haan, E. (Department of Paediatrics. University of Adelaide)
Hernández, Isabel (Institut Català de Neurociènces Aplicades)
Ruiz, A. (Institut Català de Neurociènces Aplicades)
Boada, Mercè (Institut Català de Neurociènces Aplicades)
Borroni, Barbara (Neurology Clinic. University of Brescia)
Padovani, Alessandro (Neurology Clinic. University of Brescia)
Cruchaga, Carlos (Hope Center. Washington University School of Medicine)
Cairns, Nigel J (Department of Pathology and Immunology. Washington University)
Benussi, Luisa (Molecular Markers Laboratory. IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli)
Binetti, Giuliano (MAC Memory Clinic. IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli)
Ghidoni, R. (Molecular Markers Laboratory. IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli)
Forloni, G. (Biology of Neurodegenerative Disorders. IRCCS Istituto di Ricerche Farmacologiche "Mario Negri")
Albani, Diego (Biology of Neurodegenerative Disorders. IRCCS Istituto di Ricerche Farmacologiche "Mario Negri")
Galimberti, Daniela (Fondazione Cà Granda. IRCCS Ospedale Maggiore Policlinico)
Fenoglio, Chiara (Fondazione Cà Granda. IRCCS Ospedale Maggiore Policlinico)
Serpente, M. (Fondazione Cà Granda. IRCCS Ospedale Maggiore Policlinico)
Scarpini, E. (Fondazione Cà Granda. IRCCS Ospedale Maggiore Policlinico)
Clarimón, Jordi (Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas)
Lleó, Alberto (Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas)
Blesa, Rafael (Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas)
Landqvist Waldö, M. (Unit of Geriatric Psychiatry. Department of Clinical Sciences. Lund University)
Nilsson, K. (Unit of Geriatric Psychiatry. Department of Clinical Sciences. Lund University)
Nilsson, C. (Clinical Memory Research Unit. Department of Clinical Sciences. Lund University)
Mackenzie, I. R. A. (Department of Pathology and Laboratory Medicine. University of British Columbia)
Hsiung, G. Y. R. (Division of Neurology. University of British Columbia)
Mann, D. M. A. (Institute of Brain. Behaviour and Mental Health. University of Manchester. Salford Royal Hospital)
Grafman, J. (Department of Psychology. Weinberg College of Arts and Sciences. Northwestern University)
Morris, C. M. (Newcastle University. Institute of Neuroscience and Institute for Ageing)
Attems, Johannes (Newcastle University. Institute of Neuroscience and Institute for Ageing)
Griffiths, T. D. (Newcastle University. Institute of Neuroscience and Institute for Ageing)
McKeith, I. G. (Newcastle University. Institute of Neuroscience and Institute for Ageing)
Thomas, A. J. (Newcastle University. Institute of Neuroscience and Institute for Ageing)
Pietrini, P. (IMT School for Advanced Studies. Lucca)
Huey, Edward D (Taub Institute. Departments of Psychiatry and Neurology. Columbia University)
Wassermann, E. M. (Behavioral Neurology Unit. National Insititute of Neurological Disorders and Stroke. National Insititutes of Health)
Baborie, A. (Department of Laboratory Medicine & Pathology. University of Alberta Edmonton)
Jaros, E. (Institute of Neuroscience and Institute for Ageing. Campus for Ageing and Vitality. Newcastle University)
Tierney, M. C. (Behavioral Neurology Unit. National Insititute of Neurological Disorders and Stroke. National Insititutes of Health)
Pastor, Pau (Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas)
Razquin, C. (Neurogenetics Laboratory. Division of Neurosciences. Center for Applied Medical Research. Universidad de Navarra)
Ortega-Cubero, S. (Neurogenetics Laboratory. Division of Neurosciences. Center for Applied Medical Research. Universidad de Navarra)
Alonso, E. (Clínica Universidad de Navarra)
Perneczky, Robert (Department of Psychiatry and Psychotherapy. Technische Universität München)
Diehl-Schmid, Janine (Department of Psychiatry and Psychotherapy. Technische Universität München)
Alexopoulos, Panagiotis (Department of Psychiatry and Psychotherapy. Technische Universität München)
Kurz, A. (Department of Psychiatry and Psychotherapy. Technische Universität München)
Rainero, Innocenzo (Neurology I. Department of Neuroscience. University of Torino. Italy. A.O. Città della Salute e della Scienza di Torino)
Rubino, E. (Neurology I. Department of Neuroscience. University of Torino. Italy. A.O. Città della Salute e della Scienza di Torino)
Pinessi, L. (Neurology I. Department of Neuroscience. University of Torino. Italy. A.O. Città della Salute e della Scienza di Torino)
Rogaeva, Ekaterina (University of Toronto. Tanz Centre for Research in Neurodegenerative Diseases)
St George Hyslop, Peter (Cambridge Institute for Medical Research)
Rossi, G. (Fondazione IRCCS Istituto Neurologico Carlo Besta)
Tagliavini, Fabrizio (Fondazione IRCCS Istituto Neurologico Carlo Besta)
Giaccone, Giorgio (Fondazione IRCCS Istituto Neurologico Carlo Besta)
Rowe, J. B. (Behavioural and Clinical Neuroscience Institute)
Schlachetzki, J. C. M. (University of California San Diego. Department of Cellular & Molecular Medicine)
Uphill, J. (UCL Institute of Neurology (Regne Unit). Department of Neurodegenerative Disease)
Collinge, John (UCL Institute of Neurology (Regne Unit). Department of Neurodegenerative Disease)
Mead, S. (UCL Institute of Neurology (Regne Unit). Department of Neurodegenerative Disease)
Danek, Adrian (Ludwig-Maximilians-Universität München)
Van Deerlin, V. M. (University of Pennsylvania Perelman School of Medicine)
Grossman, Murray (Department of Neurology and Penn Frontotemporal Degeneration Center. University of Pennsylvania Perelman School of Medicine)
Trojanowski, J. Q. (Laboratory of Neurogenetics. Institute Born-Bunge. University of Antwerp)
Van der Zee, Julie (Laboratory of Neurogenetics. Institute Born-Bunge. University of Antwerp)
Cruts, Marc (Laboratory of Neurogenetics. Institute Born-Bunge. University of Antwerp)
Van Broeckhoven, C. (Laboratory of Neurogenetics. Institute Born-Bunge. University of Antwerp)
Cappa, S. F. (Neurorehabilitation Unit. Department of Clinical Neuroscience. Vita-Salute University and San Raffaele Scientific Institute)
Leber, Isabelle (CNRS UMR 7225. F-75013)
Hannequin, D. (Service de Neurologie. Inserm U1079. CNR-MAJ. Rouen University Hospital)
Golfier, V. (Service de Neurologie. CH Saint Brieuc)
Vercelletto, M. (Service de neurologie. CHU de Nantes)
Brice, Alexis (CNRS UMR 7225. F-75013)
Nacmias, Benedetta (University of Florence. Department of Neurosciences)
Sorbi, Sandro (University of Florence. Department of Neurosciences)
Bagnoli, Silvia (University of Florence. Department of Neurosciences)
Piaceri, I. (University of Florence. Department of Neurosciences)
Nielsen, J. E. (Department of Cellular and Molecular Medicine. Section of Neurogenetics. The Panum Institute. University of Copenhagen)
Hjermind, L. E. (Department of Cellular and Molecular Medicine. Section of Neurogenetics. The Panum Institute. University of Copenhagen)
Riemenschneider, M. (Laboratory for Neurogenetics. Saarland University)
Mayhaus, M. (Laboratory for Neurogenetics. Saarland University)
Ibach, B. (Department of Psychiatry. Psychotherapy and Psychosomatics)
Gasparoni, G. (Laboratory for Neurogenetics. Saarland University)
Pichler, S. (Laboratory for Neurogenetics. Saarland University)
Gu, W. (Luxembourg Centre For Systems Biomedicine (LCSB). University of Luxembourg)
Rossor, M. N. (Dementia Research Centre. Department of Neurodegenerative Disease. UCL Institute of Neurology)
Fox, N. C. (Dementia Research Centre. Department of Neurodegenerative Disease. UCL Institute of Neurology)
Warren, J. D. (Dementia Research Centre. Department of Neurodegenerative Disease. UCL Institute of Neurology)
Spillantini, M. G. (University of Cambridge. Department of Clinical Neurosciences)
Morris, H. R. (UCL Institute of Neurology (Regne Unit). Department of Molecular Neuroscience)
Rizzu, P. (Tübingen Site. German Center for Neurodegenerative Diseases)
Heutink, Peter (Tübingen Site. German Center for Neurodegenerative Diseases)
Snowden, J. S. (Institute of Brain. Behaviour and Mental Health. University of Manchester. Salford Royal Hospital)
Rollinson, Sara (Institute of Brain. Behaviour and Mental Health. University of Manchester. Salford Royal Hospital)
Richardson, A. (Salford Royal Foundation Trust. Faculty of Medical and Human Sciences. University of Manchester)
Gerhard, A. (Institute of Brain. Behaviour and Mental Health. University of Manchester. Salford Royal Hospital)
Bruni, A. C. (Regional Neurogenetic Centre. ASPCZ)
Maletta, Raffaele (Regional Neurogenetic Centre. ASPCZ)
Frangipane, F. (Regional Neurogenetic Centre. ASPCZ)
Cupidi, C. (Regional Neurogenetic Centre. ASPCZ)
Bernardi, Livia (Regional Neurogenetic Centre. ASPCZ)
Anfossi, Maria (Regional Neurogenetic Centre. ASPCZ)
Gallo, M. (Regional Neurogenetic Centre. ASPCZ)
Conidi, Maria E. (Regional Neurogenetic Centre. ASPCZ)
Smirne, N. (Regional Neurogenetic Centre. ASPCZ)
Rademakers, Rosa (Department of Neuroscience. Mayo Clinic Jacksonville)
Baker, M. (Department of Neuroscience. Mayo Clinic Jacksonville)
Dickson, Dennis W. (Department of Neuroscience. Mayo Clinic Jacksonville)
Graff-Radford, N. R. (Department of Neuroscience. Mayo Clinic Jacksonville)
Petersen, R. C. (Department of Neurology. Mayo Clinic Rochester)
Knopman, D. (Department of Neurology. Mayo Clinic Rochester)
Josephs, K. A. (Department of Neurology. Mayo Clinic Rochester)
Boeve, Bradley (Department of Neurology. Mayo Clinic Rochester)
Parisi, J. E. (Department of Pathology. Mayo Clinic Rochester)
Karydas, A. M. (University of California, San Francisco (UCSF))
Rosen, H. (University of California, San Francisco (UCSF))
van Swieten, J. C. (Department of Medical Genetics. VU university Medical Centre)
Dopper, E. G. P. (Department of Medical Genetics. VU university Medical Centre)
Seelaar, H. (Department of Medical Genetics. VU university Medical Centre)
Pijnenburg, Y. A. L. (VU University Medical Centre. Department of Neurology)
Scheltens, Philip (VU University Medical Centre. Department of Neurology)
Logroscino, Giancarlo (Department of Basic Medical Sciences. Neurosciences and Sense Organs. "Aldo Moro" University of Bari)
Capozzo, Rosa (University of Bari)
Novelli, V. (Medical Genetics Unit. Fondazione Policlinico Universitario A. Gemelli)
Puca, A. A. (Department of Medicine and Surgery. University of Salerno)
Franceschi, M. (Neurology Department. IRCCS Multimedica)
Postiglione, A. (Department of Clinical Medicine and Surgery. University of Naples Federico II)
Milan, G. (Geriatric Center Frullone ASL Napoli 1 Centro)
Sorrentino, P. (Geriatric Center Frullone ASL Napoli 1 Centro)
Kristiansen, M. (UCL Genomics. Institute of Child Health (ICH). UCL)
Chiang, H. H. (Karolinska University Hospital and Karolinska Institutet (Suècia))
Graff, C. (Karolinska University Hospital and Karolinska Institutet (Suècia))
Pasquier, Florence (Université des Sciences et Technologies de Lille. Inserm 1171. DISTALZ. CHU 59000)
Rollin, A. (Université des Sciences et Technologies de Lille. Inserm 1171. DISTALZ. CHU 59000)
Deramecourt, Vincent (Université des Sciences et Technologies de Lille. Inserm 1171. DISTALZ. CHU 59000)
Lebouvier, Thibaud (Université des Sciences et Technologies de Lille. Inserm 1171. DISTALZ. CHU 59000)
Kapogiannis, D. (National Institute on Aging (NIA/NIH))
Ferrucci, Luigi (National Institute on Aging (Baltimore, Estats Units d'Amèrica))
Pickering-Brown, S. (University of Manchester)
Singleton, Andrew B (National Institute on Aging (Bethesda, Estats Units d'Amèrica))
Universitat Autònoma de Barcelona

Fecha:	2019
Resumen:	The semantic variant of primary progressive aphasia (svPPA) is a clinical syndrome characterized by neurodegeneration and progressive loss of semantic knowledge. Unlike many other forms of frontotemporal lobar degeneration (FTLD), svPPA has a highly consistent underlying pathology composed of TDP-43 (a regulator of RNA and DNA transcription metabolism). Previous genetic studies of svPPA are limited by small sample sizes and a paucity of common risk variants. Despite this, svPPA's relatively homogenous clinicopathologic phenotype makes it an ideal investigative model to examine genetic processes that may drive neurodegenerative disease. In this study, we used GWAS metadata, tissue samples from pathologically confirmed frontotemporal lobar degeneration, and in silico techniques to identify and characterize protein interaction networks associated with svPPA risk. We identified 64 svPPA risk genes that interact at the protein level. The protein pathways represented in this svPPA gene network are critical regulators of RNA metabolism and cell death, such as SMAD proteins and NOTCH1. Many of the genes in this network are involved in TDP-43 metabolism. Contrary to the conventional notion that svPPA is a clinical syndrome with few genetic risk factors, our analyses show that svPPA risk is complex and polygenic in nature. Risk for svPPA is likely driven by multiple common variants in genes interacting with TDP-43, along with cell death,x' working in combination to promote neurodegeneration.
Derechos:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Lengua:	Anglès
Documento:	Article ; recerca ; Versió publicada
Materia:	Gene expression ; Genetic association study ; Dementia ; Neurodegenerative diseases
Publicado en:	Scientific reports, Vol. 9 Núm. 1 (january 2019) , p. 10854, ISSN 2045-2322

DOI: 10.1038/s41598-019-46415-1
PMID: 31350420

10 p, 1.3 MB

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