Genome-wide analyses reveal a potential role for the MAPT, MOBP, and APOE loci in sporadic frontotemporal dementia
Manzoni, Claudia (University College London School of Pharmacy)
Kia, Demis A. (Department of Clinical and Movement. Neurosciences. UCL Queen Square Institute of Neurology (Londres, Regne Unit))
Ferrari, Raffaele (Department of Clinical and Movement. Neurosciences. UCL Queen Square Institute of Neurology (Londres, Regne Unit))
Leonenko, Ganna (Division of Psychological Medicine and Clinical Neurosciences. UK Dementia Research Institute. School of Medicine. Cardiff University (Cardiff, Regne Unit))
Costa, Beatrice (Department of Clinical and Movement. Neurosciences. UCL Queen Square Institute of Neurology (Londres, Regne Unit))
Saba, Valentina (Medical and Genomic Statistics Unit. Department of Brain and Behavioral Sciences. University of Pavia (Itàlia))
Jabbari, Edwin (Department of Clinical and Movement. Neurosciences. UCL Queen Square Institute of Neurology (Londres, Regne Unit))
Tan, Manuela (Oslo University Hospital (Oslo, Noruega))
Albani, Diego (Istituto di Ricerche Farmacologiche Mario Negri IRCCS (Milà, Itàlia))
Alvarez, Victoria (Instituto de Investigación Sanitaria del Principado de Asturias)
Alvarez, Ignacio (Fundació Docència i Recerca Mútua Terrassa)
Andreassen, Ole A. (Division of Mental Health and Addiction. Oslo University Hospital)
Angiolillo, Antonella (Centre for Research and Training in Medicine of Aging. Department of Medicine and Health Science "V. Tiberio. " University of Molise)
Arighi, Andrea (Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico (Milà, Itàlia))
Baker, Matt (Mayo Clinic Florida (Jacksonville, Estats Units d'Amèrica). Department of Neuroscience)
Benussi, Luisa (IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli (Brescia, Itàlia))
Bessi, Valentina (Department of Neuroscience. Psychology. Drug Research and Child Health. University of Florence)
Binetti, Giuliano (IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli (Brescia, Itàlia))
Blackburn, Daniel J. (University of Sheffield)
Boada, Mercè (Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas)
Boeve, Bradley (Mayo Clinic (Rochester, Estats Units d'Amèrica). Department of Neurology)
Borrego-Écija, Sergi (Institut d'Investigacions Biomèdiques August Pi i Sunyer)
Borroni, Barbara (Department of Clinical and Experimental Sciences. University of Brescia)
Bråthen, Geir (Department of Neuromedicine and Movement Science. Faculty of Medicine and Health Sciences. Norwegian University of Science and Technology)
Brooks, William S. (Neuroscience Research Australia. Randwick Clinical Campus. UNSW Medicine and Health. University of New South Wales)
Bruni, Amalia (Regional Neurogenetic Centre. ASPCZ)
Caroppo, Paola (Fondazione IRCCS Istituto Neurologico Carlo Besta (Milà, Itàlia))
Bandres-Ciga, Sara (Center for Alzheimer's and Related Dementias. National Institute on Aging and National Institute of Neurological Disorders and Stroke. National Institutes of Health)
Clarimón, Jordi (Hospital de la Santa Creu i Sant Pau (Barcelona, Catalunya))
Colao, Rosanna (Regional Neurogenetic Centre. ASPCZ)
Cruchaga, Carlos (Washington University School of Medicine)
Danek, Adrian (Ludwig-Maximilians-Universität München)
de Boer, Sterre C. (Brain and Mind Centre. University of Sydney)
De Rojas, Itziar (Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas)
di Costanzo, Alfonso (Centre for Research and Training in Medicine of Aging. Department of Medicine and Health Science "V. Tiberio. " University of Molise)
Dickson, Dennis W. (Mayo Clinic Florida (Jacksonville, Estats Units d'Amèrica). Department of Neuroscience)
Diehl-Schmid, Janine (kbo-Inn-Salzach-Klinikum)
Dobson-Stone, Carol (School of Medical Sciences. University of Sydney)
Dols Icardo, Oriol (Institut de Recerca Sant Pau)
Donizetti, Aldo (Department of Biology. University of Naples Federico II)
Dopper, Elise (Department of Neurology & Alzheimer Center. Erasmus University Medical Center)
Durante, Elisabetta (Immunohematology and Transfusional Medicine Service. Local Health Authority n.2 Marca Trevigiana)
Ferrari, Camilla (Department of Neuroscience. Psychology. Drug Research and Child Health. University of Florence)
Forloni, Gianluigi (IRCCS Istituto Giannina Gaslini (Gènova, Itàlia))
Frangipane, Francesca (Regional Neurogenetic Centre. ASPCZ)
Fratiglioni, Laura (Theme Inflammation and Aging. Karolinska Universtiy Hospital)
Kramberger, Milica G. (Karolinska Institutet. Department of Neurobiology. Care Sciences and Society (NVS). Division of Clinical Geriatrics)
Galimberti, Daniela (University of Milan)
Gallucci, Maurizio (Cognitive Impairment Center. Local Health Authority n.2 Marca Trevigiana)
García-González, Pablo (Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas)
Ghidoni, Roberta (IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli (Brescia, Itàlia))
Giaccone, Giorgio (Fondazione IRCCS Istituto Neurologico Carlo Besta (Milà, Itàlia))
Graff, Caroline (Unit for hereditary dementia. Karolinska Universtiy Hospital-Solna)
Graff-Radford, Neill R. (Mayo Clinic Florida (Jacksonville, Estats Units d'Amèrica). Department of Neurology)
Grafman, Jordan (Shirley Ryan AbilityLab)
Halliday, Glenda M. (School of Medical Sciences. University of Sydney)
Hernandez, Dena G. (National Institute on Aging (Bethesda, Estats Units d'Amèrica))
Hjermind, Lena E. (Danish Dementia Research Centre)
Hodges, John R. (Brain and Mind Centre. University of Sydney)
Holloway, Guy (Anne Rowling Regenerative Neurology Clinic. University of Edinburgh)
Huey, Edward D. (Bio Med Psychiatry & Human Behavior. Brown University)
Illán-Gala, Ignacio (Institut de Recerca Sant Pau)
Josephs, Keith A. (Mayo Clinic (Rochester, Estats Units d'Amèrica). Department of Neurology)
Knopman, David S. (Mayo Clinic (Rochester, Estats Units d'Amèrica). Department of Neurology)
Kristiansen, Mark (Zayed Centre for Research into Rare Disease in Children)
Kwok, John B. (School of Medical Sciences. University of Sydney)
Leber, Isabelle (AP-HP Sorbonne Université. Pitié-Salpêtrière Hospital. Department of Neurology. Institute of Memory and Alzheimer's Disease)
Leonard, Hampton L. (DZNE Tübingen (Alemanya))
Libri, Ilenia (Department of Clinical and Experimental Sciences. University of Brescia)
Lleó, Alberto (Institut de Recerca Sant Pau)
Mackenzie, Ian R. (Vancouver Coastal Health. Department of Pathology)
Madhan, Gaganjit K. (Zayed Centre for Research into Rare Disease in Children)
Maletta, Raffaele (Regional Neurogenetic Centre. ASPCZ)
Marquié, Marta (Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas)
Maver, Ales (Clinical institute of Genomic Medicine. University Medical Center Ljubljana)
Menendez-Gonzalez, Manuel (Universidad de Oviedo. Medicine Department)
Milan, Graziella (Geriatric Center "Frullone" ASL NA1)
Miller, Bruce L. (Trinity College Dublin)
Morris, Christopher M. (Newcastle Brain Tissue Resource. Newcastle University)
Morris, Huw (Department of Clinical and Movement. Neurosciences. UCL Queen Square Institute of Neurology)
Nacmias, Benedetta (IRCCS Fondazione Don Carlo Gnocchi)
Newton, Judith (Anne Rowling Regenerative Neurology Clinic. University of Edinburgh)
Nielsen, Jørgen E. (Danish Dementia Research Centre)
Nilsson, Christer (Department of Clinical Sciences. Neurology. Lund University)
Novelli, Valeria (Centro Cardiologico Monzino IRCCS)
Padovani, Alessandro (University of Brescia)
Pal, Suvankar (Anne Rowling Regenerative Neurology Clinic. University of Edinburgh)
Pasquier, Florence (Inserm. Labex DISTALZ. LiCEND)
Pastor, Pau (Institut Germans Trias i Pujol)
Perneczky, Robert (Sheffield Institute for Translational Neuroscience (SITraN). University of Sheffield)
Peterlin, Borut (Clinical institute of Genomic Medicine. University Medical Center Ljubljana)
Petersen, Ronald C. (Mayo Clinic (Rochester, Estats Units d'Amèrica). Department of Neurology)
Piguet, Olivier (School of Psychology. University of Sydney)
Pijnenburg, Yolande AL. (Amsterdam University Medical Center (UMC))
Puca, Annibale A. (IRCCS MultiMedica (Milà, Itàlia))
Rademakers, Rosa (Department of Biomedical Sciences. University of Antwerp)
Rainero, Innocenzo (AOU Città della Salute e della Scienza di Torino)
Reus, Lianne (Center for Neurobehavioral Genetics. Semel Institute for Neuroscience and Human Behavior. University of California. Los Angeles)
Richardson, Anna MT. (Manchester Centre for Clinical Neurosciences. Northern Care Alliance NHS Trust. Manchester Academic Health Sciences Unit. University of Manchester)
Riemenschneider, Matthias (Department of Psychiatry. Saarland University)
Rogaeva, Ekaterina (Tanz Centre for Research in Neurodegenerative Diseases and Department of Medicine. University of Toronto)
Rogelj, Boris (Univerza V Ljubljana)
Rollinson, Sara (University of Manchester)
Rosen, Howard (Department of Neurology. University of California. San Francisco)
Rossi, Giacomina (Fondazione IRCCS Istituto Neurologico Carlo Besta (Milà, Itàlia))
Rowe, James B. (University of Cambridge Department of Clinical Neurosciences and Cambridge University Hospitals NHS Trust)
Rubino, Elisa (AOU Città della Salute e della Scienza di Torino)
Ruiz Laza, Agustín (Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas)
Salvi, Erika (Fondazione IRCCS Istituto Neurologico Carlo Besta (Milà, Itàlia))
Sanchez-Valle, Raquel (Institut d'Investigacions Biomèdiques August Pi i Sunyer)
Sando, Sigrid Botne (Department of Neuromedicine and Movement Science. Faculty of Medicine and Health Sciences. Norwegian University of Science and Technology)
Santillo, Alexander F. (Lund University. Department of Clinical Sciences)
Saxon, Jennifer A. (Manchester Centre for Clinical Neurosciences)
Schlachetzki, Johannes CM. (Department of Cellular and Molecular Medicine. University of California. San Diego)
Scholz, Sonja (Department of Neurology. Johns Hopkins University Medical Center)
Seelaar, Harro (Erasmus University Medical Center Rotterdam (Països Baixos))
Seeley, William W. (Department of Neurology. University of California. San Francisco)
Serpente, Maria (Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico (Milà, Itàlia))
Sorbi, Sandro (IRCCS Fondazione Don Carlo Gnocchi)
Sordon, Sabrina (Department of Psychiatry. Saarland University)
St George-Hyslop, Peter (Department of Neurology. Columbia University)
Thompson, Jennifer C. (Division of Neuroscience and Experimental Psychology. School of Biological Sciences. University of Manchester)
Van Broeckhoven, Christine (VIB Center for Molecular Neurology (Bèlgica, Païssos Baixos))
Van Deerlin, Vivianna (Perelman School of Medicine at the University of Pennsylvania)
van der Lee, Sven J. (Vrije Universiteit Amsterdam. Department of Clinical Genetics)
van Swieten, John (Erasmus University Medical Center)
Tagliavini, Fabrizio (Fondazione IRCCS Istituto Neurologico Carlo Besta (Milà, Itàlia))
Van der Zee, Julie (VIB Center for Molecular Neurology)
Veronesi, Arianna (Immunohematology and Transfusional Medicine Service. Local Health Authority n.2 Marca Trevigiana)
Vitale, Emilia (School of Integrative Science and Technology Department of Biology Kean University)
Waldo, Maria Landqvist (Clinical Sciences Helsingborg. Department of Clinical Sciences. Lund University (Suècia))
Yokoyama, Jennifer S. (Department of Radiology and Biomedical Imaging. University of California. San Francisco)
Nalls, Mike A. (Data Tecnica International LLC (Estats Units d'Amèrica))
Momeni, Parastoo (Rona Holdings (Estats Units d'Amèrica))
Singleton, Andrew B. (National Institute on Aging (Bethesda, Estats Units d'Amèrica))
Hardy, John (Institute for Advanced Study. The Hong Kong University of Science and Technology)
Escott-Price, Valentina (Division of Psychological Medicine and Clinical Neurosciences. UK Dementia Research Institute. School of Medicine. Cardiff University (Cardiff, Regne Unit))
Universitat Autònoma de Barcelona

Date:	2024
Abstract:	Frontotemporal dementia (FTD) is the second most common cause of early-onset dementia after Alzheimer disease (AD). Efforts in the field mainly focus on familial forms of disease (fFTDs), while studies of the genetic etiology of sporadic FTD (sFTD) have been less common. In the current work, we analyzed 4,685 sFTD cases and 15,308 controls looking for common genetic determinants for sFTD. We found a cluster of variants at the MAPT (rs199443; p = 2. 5 × 10, OR = 1. 27) and APOE (rs6857; p = 1. 31 × 10, OR = 1. 27) loci and a candidate locus on chromosome 3 (rs1009966; p = 2. 41 × 10, OR = 1. 16) in the intergenic region between RPSA and MOBP, contributing to increased risk for sFTD through effects on expression and/or splicing in brain cortex of functionally relevant in-cis genes at the MAPT and RPSA-MOBP loci. The association with the MAPT (H1c clade) and RPSA-MOBP loci may suggest common genetic pleiotropy across FTD and progressive supranuclear palsy (PSP) (MAPT and RPSA-MOBP loci) and across FTD, AD, Parkinson disease (PD), and cortico-basal degeneration (CBD) (MAPT locus). Our data also suggest population specificity of the risk signals, with MAPT and APOE loci associations mainly driven by Central/Nordic and Mediterranean Europeans, respectively. This study lays the foundations for future work aimed at further characterizing population-specific features of potential FTD-discriminant APOE haplotype(s) and the functional involvement and contribution of the MAPT H1c haplotype and RPSA-MOBP loci to pathogenesis of sporadic forms of FTD in brain cortex.
Note:	Altres ajuts: Research grants from Parkinson\u2019s UK, Cure Parkinson\u2019s Trust, PSP Association, Medical Research Council, and the Michael J. Fox Foundation. H.R.M. is a co-applicant on a patent application related to C9ORF72\u2014Method for diagnosing a neurodegenerative disease (PCT/GB2012/052140). This work was funded by the Alzheimer\u2019s Society (grant number 284 to R.F.). Additional funding info and acknowledgments can be found in the supplemental information.
Rights:	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.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	Aged ; Apolipoproteins E ; Case-Control Studies ; Female ; Frontotemporal Dementia ; Genetic Loci ; Genetic Predisposition to Disease ; Genome-Wide Association Study ; Humans ; Male ; Middle Aged ; Myelin Proteins ; Polymorphism, Single Nucleotide ; Tau Proteins
Published in:	American Journal of Human Genetics, Vol. 111 Núm. 7 (november 2024) , p. 1316-1329, ISSN 1537-6605

DOI: 10.1016/j.ajhg.2024.05.017
PMID: 38889728

15 p, 2.5 MB

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