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)
Steele, Natasha Z. R. (University of California)
Karch, Celeste M. (Washington University)
Broce, Iris (University of California)
Geier, Ethan G. (University of California)
Wen, Natalie L. (Washington University)
Momeni, Parastoo (Texas Tech University Health Science Center)
Hardy, John (UCL Institute of Neurology (Regne Unit). Department of Molecular Neuroscience)
Miller, Zachary A. (University of California)
Gorno-Tempini, Maria Luisa (University of California)
Hess, Christopher P. (University of California)
Lewis, Patrick (University of Reading)
Miller, Bruce L. (University of California)
Seeley, William W. (University of California)
Manzoni, Claudia (University of Reading)
Desikan, Rahul S. (University of California)
Baranzini, Sergio E. (University of California)
Ferrari, Raffaele (UCL Institute of Neurology (Regne Unit). Department of Molecular Neuroscience)
Yokoyama, Jennifer S. (University of California)
Hernandez, D. G. (UCL Institute of Neurology (Regne Unit))
Nalls, M. A. (National Institute on Aging (Bethesda, Estats Units d'Amèrica))
Rohrer, J. D. (University College London. Institute of Neurology)
Ramasamy, Adaikalavan (The Jenner Institute. University of Oxford)
Kwok, John B.J. (University of New South Wales)
Dobson-Stone, Carol (University of New South Wales)
Schofield, P. R. (University of New South Wales)
Halliday, G. M. (University of New South Wales)
Hodges, J. R. (University of New South Wales)
Piguet, O. (University of New South Wales)
Bartley, Lauren (University of New South Wales)
Thompson, E. (University of Adelaide)
Haan, Eric (University of Adelaide)
Hernández, Isabel (Institut Català de Neurociènces Aplicades)
Ruiz Laza, Agustín (Institut Català de Neurociències Aplicades)
Boada, Mercè (Institut Català de Neurociènces Aplicades)
Borroni, Barbara (Università degli Studi di Brescia)
Padovani, Alessandro (Università degli Studi di Brescia)
Cruchaga, Carlos (Hope Center. Washington University School of Medicine)
Cairns, Nigel J. (Washington University)
Benussi, Luisa (IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli (Brescia, Itàlia))
Binetti, Giuliano (IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli (Brescia, Itàlia))
Ghidoni, Roberta (IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli (Brescia, Itàlia))
Forloni, G. (IRCCS Istituto Giannina Gaslini (Gènova, Itàlia))
Albani, Diego (IRCCS Istituto Giannina Gaslini (Gènova, Itàlia))
Galimberti, Daniela (Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico (Milà, Itàlia))
Fenoglio, Chiara (Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico (Milà, Itàlia))
Serpente, M. (Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico (Milà, Itàlia))
Scarpini, Elio (Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico (Milà, Itàlia))
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. (Lund University)
Nilsson, K. (Lund University)
Nilsson, C. (Lund University)
Mackenzie, I. R. A. (University of British Columbia)
Hsiung, G. Y. R. (University of British Columbia)
Mann, D. M. A. (University of Manchester)
Grafman, J. (Northwestern University)
Morris, C. M. (Newcastle University)
Attems, Johannes (Newcastle University)
Griffiths, T. D. (Newcastle University)
McKeith, I. G. (Newcastle University)
Thomas, A. J. (Newcastle University)
Pietrini, P. (IMT School for Advanced Studies)
Huey, Edward D. (Columbia University)
Wassermann, Eric (National Insititutes of Health)
Baborie, Atik (University of Alberta Edmonton)
Jaros, Evelyn (Newcastle University)
Tierney, M. C. (National Insititutes of Health)
Pastor, Pau (Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas)
Razquin, C. (Universidad de Navarra)
Ortega-Cubero, S. (Universidad de Navarra)
Alonso, Elena (Clínica Universidad de Navarra)
Perneczky, Robert (Technische Universität München. Department of Psychiatry and Psychotherapy)
Diehl-Schmid, Janine (Technische Universität München. Department of Psychiatry and Psychotherapy)
Alexopoulos, Panagiotis (Technische Universität München. Department of Psychiatry and Psychotherapy)
Kurz, A. (Technische Universität München. Department of Psychiatry and Psychotherapy)
Rainero, Innocenzo (Università di Torino)
Rubino, E. (Neurology I. Università di Torino)
Pinessi, Lorenzo (Neurology I. Università di Torino)
Rogaeva, Ekaterina (University of Toronto. Tanz Centre for Research in Neurodegenerative Diseases)
St George Hyslop, Peter (Cambridge Institute for Medical Research)
Rossi, Giacomina (Fondazione IRCCS Istituto Neurologico Carlo Besta (Milà, Itàlia))
Tagliavini, Fabrizio (Fondazione IRCCS Istituto Neurologico Carlo Besta (Milà, Itàlia))
Giaccone, Giorgio (Fondazione IRCCS Istituto Neurologico Carlo Besta (Milà, Itàlia))
Rowe, J. B. (Behavioural and Clinical Neuroscience Institute)
Schlachetzki, J. C. M. (University of California San Diego. Department of Cellular & Molecular Medicine)
Uphill, James B. (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 (University of Pennsylvania Perelman School of Medicine)
Trojanowski, J. Q. (University of Antwerp)
Van der Zee, Julie (University of Antwerp)
Cruts, Marc (University of Antwerp)
Van Broeckhoven, Christine (University of Antwerp)
Cappa, S. F. (Vita-Salute University and San Raffaele Scientific Institute)
Leber, Isabelle
Hannequin, D. (Rouen University Hospital (França))
Golfier, Véronique (CH Saint Brieuc)
Vercelletto, M. (CHU de Nantes)
Brice, Alexis
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. (University of Copenhagen)
Hjermind, L. E. (University of Copenhagen)
Riemenschneider, M. (Saarland University)
Mayhaus, M. (Saarland University)
Ibach, B.
Gasparoni, G. (Saarland University)
Pichler, S. (Saarland University)
Gu, Wei (Luxembourg Centre For Systems Biomedicine (LCSB))
Rossor, M. N. (University College London. Institute of Neurology)
Fox, N. C. (University College London. Institute of Neurology)
Warren, J. D. (University College London. 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. (University of Manchester)
Rollinson, Sara (University of Manchester)
Richardson, A. (University of Manchester)
Gerhard, Alexander (University of Manchester)
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, Nicoletta (Regional Neurogenetic Centre. ASPCZ)
Rademakers, Rosa (Mayo Clinic Florida (Jacksonville, Estats Units d'Amèrica). Department of Neuroscience)
Baker, M. (Mayo Clinic Florida (Jacksonville, Estats Units d'Amèrica). Department of Neuroscience)
Dickson, Dennis W. (Mayo Clinic Florida (Jacksonville, Estats Units d'Amèrica). Department of Neuroscience)
Graff-Radford, N. R. (Mayo Clinic Florida (Jacksonville, Estats Units d'Amèrica). Department of Neuroscience)
Petersen, R. C. (Mayo Clinic (Rochester, Estats Units d'Amèrica). Department of Neurology)
Knopman, D. (Mayo Clinic (Rochester, Estats Units d'Amèrica). Department of Neurology)
Josephs, K. A. (Mayo Clinic (Rochester, Estats Units d'Amèrica). Department of Neurology)
Boeve, Bradley (Mayo Clinic (Rochester, Estats Units d'Amèrica). Department of Neurology)
Parisi, J. E. (Mayo Clinic (Rochester, Estats Units d'Amèrica))
Karydas, A. M. (University of California, San Francisco (UCSF))
Rosen, H. (University of California, San Francisco (UCSF))
van Swieten, J. C. (VU university Medical Centre)
Dopper, E. G. P. (VU university Medical Centre)
Seelaar, H. (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 ("Aldo Moro" University of Bari)
Capozzo, Rosa (University of Bari)
Novelli, V. (Fondazione Policlinico Universitario A. Gemelli)
Puca, A. A. (Università degli Studi di Salerno)
Franceschi, M. (IRCCS Multimedica)
Postiglione, A. (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, Caroline (Karolinska University Hospital and Karolinska Institutet (Suècia))
Pasquier, Florence (Université des Sciences et Technologies de Lille.)
Rollin, A. (Université des Sciences et Technologies de Lille)
Deramecourt, Vincent (Université des Sciences et Technologies de Lille)
Lebouvier, Thibaud (Université des Sciences et Technologies de Lille)
Kapogiannis, D. (National Institute on Aging (Estats Units d'Amèrica))
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

Data:	2019
Resum:	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.
Drets:	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.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	Gene expression ; Genetic association study ; Dementia ; Neurodegenerative diseases
Publicat a:	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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