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Frontotemporal dementia and its subtypes: a genome-wide association study
Open accessAbstract
Background Frontotemporal dementia (FTD) is a complex disorder characterised by a broad range of clinical manifestations, differential pathological signatures, and genetic variability. Mutations in three genes-MAPT, GRN, and C9orf72--have been associated with FTD. We sought to identify novel genetic risk loci associated with the disorder. Methods We did a two-stage genome-wide association study on clinical FTD, analysing samples from 3526 patients with FTD and 9402 healthy controls. To reduce genetic heterogeneity, all participants were of European ancestry. In the discovery phase (samples from 2154 patients with FTD and 4308 controls), we did separate association analyses for each FTD subtype (behavioural variant FTD, semantic dementia, progressive non-fluent aphasia, and FTD overlapping with motor neuron disease [FTD-MND]), followed by a meta-analysis of the entire dataset. We carried forward replication of the novel suggestive loci in an independent sample series (samples from 1372 patients and 5094 controls) and then did joint phase and brain expression and methylation quantitative trait loci analyses for the associated (p<5 × 10(-8)) single-nucleotide polymorphisms. Findings We identified novel associations exceeding the genome-wide significance threshold (p<5 × 10(-8)). Combined (joint) analyses of discovery and replication phases showed genome-wide significant association at 6p21.3, HLA locus (immune system), for rs9268877 (p=1·05 × 10(-8); odds ratio=1·204 [95% CI 1·11-1·30]), rs9268856 (p=5·51 × 10(-9); 0·809 [0·76-0·86]) and rs1980493 (p value=1·57 × 10(-8), 0·775 [0·69-0·86]) in the entire cohort. We also identified a potential novel locus at 11q14, encompassing RAB38/CTSC (the transcripts of which are related to lysosomal biology), for the behavioural FTD subtype for which joint analyses showed suggestive association for rs302668 (p=2·44 × 10(-7); 0·814 [0·71-0·92]). Analysis of expression and methylation quantitative trait loci data suggested that these loci might affect expression and methylation in cis. Interpretation Our findings suggest that immune system processes (link to 6p21.3) and possibly lysosomal and autophagy pathways (link to 11q14) are potentially involved in FTD. Our findings need to be replicated to better define the association of the newly identified loci with disease and to shed light on the pathomechanisms contributing to FTD. Funding The National Institute of Neurological Disorders and Stroke and National Institute on Aging, the Wellcome/MRC Centre on Parkinson's disease, Alzheimer's Research UK, and Texas Tech University Health Sciences Center.
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“MAPT mutations drive tau pathology”
From The Role of Retrotransposons and Endogenous Retroviruses in Age-Dependent Neurodegenerative Disorders (2024) · cites this paper as Ferrari et al. 2014
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“Age-dependent neurodegenerative disorders are clinically diverse but exhibit significant comorbidity and heterogeneous pathology both within and across disorders”
From The Role of Retrotransposons and Endogenous Retroviruses in Age-Dependent Neurodegenerative Disorders (2024) · cites this paper as Ferrari et al. 2014
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Self-citationDementias Caused by Persistent Pathogens and the Protective Role of HLA Against them
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Metadata
- Authors
- Ferrari, R., Hernandez, D. G., Nalls, M. A., Rohrer, J. D., Ramasamy, A., Kwok, J. B. J., Dobson-Stone, C., Brooks, W. S., Schofield, P. R., Halliday, G. M., Hodges, J. R., Piguet, O., Bartley, L., Thompson, E., Haan, E., Hernández, I., Ruiz, A., Boada, M., Borroni, B., Padovani, A., Cruchaga, C., Cairns, N. J., Benussi, L., Binetti, G., Ghidoni, R., Forloni, G., Galimberti, D., Fenoglio, C., Serpente, M., Scarpini, E., Clarimón, J., Lleó, A., Blesa, R., Waldö, M. L., Nilsson, K., Nilsson, C., Mackenzie, I. R. A., Hsiung, G.-Y. R., Mann, D. M. A., Grafman, J., Morris, C. M., Attems, J., Griffiths, T. D., McKeith, I. G., Thomas, A. J., Pietrini, P., Huey, E. D., Wassermann, E. M., Baborie, A., Jaros, E., Tierney, M. C., Pastor, P., Razquin, C., Ortega-Cubero, S., Alonso, E., Perneczky, R., Diehl-Schmid, J., Alexopoulos, P., Kurz, A., Rainero, I., Rubino, E., Pinessi, L., Rogaeva, E., St George-Hyslop, P., Rossi, G., Tagliavini, F., Giaccone, G., Rowe, J. B., Schlachetzki, J. C. M., Uphill, J., Collinge, J., Mead, S., Danek, A., Van Deerlin, V. M., Grossman, M., Trojanowski, J. Q., van der Zee, J., Deschamps, W., Van Langenhove, T., Cruts, M., Van Broeckhoven, C., Cappa, S. F., Le Ber, I., Hannequin, D., Golfier, V., Vercelletto, M., Brice, A., Nacmias, B., Sorbi, S., Bagnoli, S., Piaceri, I., Nielsen, J. E., Hjermind, L. E., Riemenschneider, M., Mayhaus, M., Ibach, B., Gasparoni, G., Pichler, S., Gu, W., Rossor, M. N., Fox, N. C., Warren, J. D., Spillantini, M. G., Morris, H. R., Rizzu, P., Heutink, P., Snowden, J. S., Rollinson, S., Richardson, A., Gerhard, A., Bruni, A. C., Maletta, R., Frangipane, F., Cupidi, C., Bernardi, L., Anfossi, M., Gallo, M., Conidi, M. E., Smirne, N., Rademakers, R., Baker, M., Dickson, D. W., Graff-Radford, N. R., Petersen, R. C., Knopman, D., Josephs, K. A., Boeve, B. F., Parisi, J. E., Seeley, W. W., Miller, B. L., Karydas, A. M., Rosen, H., van Swieten, J. C., Dopper, E. G. P., Seelaar, H., Pijnenburg, Y. A. L., Scheltens, P., Logroscino, G., Capozzo, R., Novelli, V., Puca, A. A., Franceschi, M., Postiglione, A., Milan, G., Sorrentino, P., Kristiansen, M., Chiang, H.-H., Graff, C., Pasquier, F., Rollin, A., Deramecourt, V., Lebert, F., Kapogiannis, D., Ferrucci, L., Pickering-Brown, S., Singleton, A. B., Hardy, J., & Momeni, P.
- Affiliations
- Texas Tech University (US)
- National Institutes of Health (US)
- National Hospital for Neurology and Neurosurgery (GB)
- Guy's Hospital (GB)
- UNSW Sydney (AU)
- Neuroscience Research Australia (AU)
- South Australia Pathology (AU)
- Fundació ACE (ES)
- University of Brescia (IT)
- Washington University in St. Louis (US)
- Centro San Giovanni di Dio Fatebenefratelli (IT)
- Mario Negri Institute for Pharmacological Research (IT)
- University of Milan (IT)
- Universitat Autònoma de Barcelona (ES)
- Lund University (SE)
- University of British Columbia (CA)
- University of Manchester (GB)
- Northwestern University (US)
- Newcastle University (GB)
- University of Pisa (IT)
- Columbia University (US)
- Walton Centre (GB)
- Royal Victoria Infirmary (GB)
- Centro de Investigación Médica Aplicada (ES)
- West London Mental Health NHS Trust (GB)
- Technical University of Munich (DE)
- Azienda Ospedaliera Citta' della Salute e della Scienza di Torino (IT)
- University of Toronto (CA)
- Fondazione IRCCS Istituto Neurologico Carlo Besta (IT)
- MRC Cognition and Brain Sciences Unit (GB)
- University of Freiburg (DE)
- MRC Prion Unit (GB)
- German Center for Neurodegenerative Diseases (DE)
- University of Pennsylvania (US)
- University of Antwerp (BE)
- Vita-Salute San Raffaele University (IT)
- Inserm (FR)
- Centre Hospitalier de Saint-Brieuc (FR)
- Centre Hospitalier Universitaire de Nantes (FR)
- Centre National de la Recherche Scientifique (FR)
- University of Florence (IT)
- University of Copenhagen (DK)
- Saarland University (DE)
- University of Regensburg (DE)
- University of Luxembourg (LU)
- University of Cambridge (GB)
- Cardiff University (GB)
- Presidio Ospedaliero Lamezia Terme (IT)
- Mayo Clinic (US)
- University of California, San Francisco (US)
- Erasmus MC (NL)
- Amsterdam UMC Location Vrije Universiteit Amsterdam (NL)
- University of Bari Aldo Moro (IT)
- Istituti Clinici Scientifici Maugeri (IT)
- University of Salerno (IT)
- MultiMedica (IT)
- Federico II University Hospital (IT)
- University College London (GB)
- Karolinska University Hospital (SE)
- Université Lille Nord de France (FR)
- National Institute on Aging (US)
- UCL Queen Square Institute of Neurology (GB)
- Corresponding author
- Hardy, John
- ORCID
- Ferrari, Raffaele
- Hernandez, Dena G
- Rohrer, Jonathan D
- Ramasamy, Adaikalavan
- Kwok, John B J
- Brooks, William S
- Schofield, Peter R
- Halliday, Glenda M
- Hodges, John R
- Piguet, Olivier
- Haan, Eric
- Borroni, Barbara
- Padovani, Alessandro
- Cruchaga, Carlos
- Cairns, Nigel J
- Benussi, Luisa
- Binetti, Giuliano
- Ghidoni, Roberta
- Forloni, Gianluigi
- Galimberti, Daniela
- Fenoglio, Chiara
- Scarpini, Elio
- Clarimón, Jordi
- Lleó, Alberto
- Blesa, Rafael
- Waldö, Maria Landqvist
- Nilsson, Karin
- Nilsson, Christer
- Mackenzie, Ian R A
- Hsiung, Ging-Yuek R
- Mann, David M A
- Grafman, Jordan
- Morris, Christopher M
- Attems, Johannes
- Griffiths, Timothy D
- McKeith, Ian G
- Thomas, Alan J
- Pietrini, P
- Huey, Edward D
- Wassermann, Eric M
- Perneczky, Robert
- Alexopoulos, Panagiotis
- Kurz, Alexander
- Rainero, Innocenzo
- Rubino, Elisa
- Pinessi, Lorenzo
- Rogaeva, Ekaterina
- Rossi, Giacomina
- Tagliavini, Fabrizio
- Giaccone, Giorgio
- Rowe, James B
- Schlachetzki, Johannes C M
- Collinge, John
- Mead, Simon
- Danek, Adrian
- Grossman, Murray
- Trojanowski, John Q
- van der Zee, Julie
- Cruts, Marc
- Cappa, Stefano F
- Hannequin, Didier
- Brice, Alexis
- Nacmias, Benedetta
- Sorbi, Sandro
- Bagnoli, Silvia
- Piaceri, Irene
- Nielsen, Jørgen E
- Hjermind, Lena E
- Gasparoni, Gilles
- Gu, Wei
- Rossor, Martin N
- Fox, Nick C
- Warren, Jason D
- Spillantini, Maria Grazia
- Morris, Huw R
- Rizzu, Patrizia
- Heutink, Peter
- Snowden, Julie S
- Rollinson, Sara
- Richardson, Anna
- Gerhard, Alexander
- Bruni, Amalia C
- Maletta, Raffaele
- Cupidi, Chiara
- Bernardi, Livia
- Anfossi, Maria
- Gallo, Maura
- Smirne, Nicoletta
- Rademakers, Rosa
- Baker, Matt
- Dickson, Dennis W
- Petersen, Ronald C
- Knopman, David
- Josephs, Keith A
- Boeve, Bradley F
- Seeley, William W
- Miller, Bruce L
- Dopper, Elise G P
- Seelaar, Harro
- Pijnenburg, Yolande A L
- Scheltens, Philip
- Logroscino, Giancarlo
- Capozzo, Rosa
- Novelli, Valeria
- Puca, Annibale A
- Franceschi, Massimo
- Milan, Graziella
- Pasquier, Florence
- Deramecourt, Vincent
- Lebert, Florence
- Kapogiannis, Dimitrios
- Ferrucci, Luigi
- Pickering-Brown, Stuart
- Singleton, Andrew B
- Hardy, John
- Venue
- The Lancet Neurology
- Publisher
- Elsevier BV
- Published
- 2014-07
- Volume
- 13
- Issue
- 7
- Pages
- 686-699
- ISSN
- 1474-4422 (ISSN-L)
- PMC
- PMC4112126
- OpenAlex
- W2152748843
- Cited by
- 383
- References
- 61
- Citations by year
- 2026: 17 · 2025: 29 · 2024: 48 · 2023: 44 · 2022: 32 · 2021: 39 · 2020: 32 · 2019: 28 · 2018: 33 · 2017: 27 · 2016: 26 · 2015: 19 · 2014: 8
- FWCI
- 20.36
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- The Lancet Neurology (publishedVersion)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (publishedVersion)
- Research Explorer (The University of Manchester) (publishedVersion)
- Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion)
- IMT Institutional Repository (IMT School for Advanced Studies Lucca) (acceptedVersion)
- PubMed Central (acceptedVersion)
- University of Regensburg Publication Server (University of Regensburg) (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Institutional Research Information System University of Turin (University of Turin) (submittedVersion)
- UNSWorks (UNSW Sydney) (submittedVersion, cc-by-nc-nd)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
- RePub (Erasmus University Rotterdam) (submittedVersion, other-oa)
- Archivio Istituzionale della Ricerca (Universita Degli Studi Di Milano) (submittedVersion, other-oa)
- CINECA IRIS Institutial research information system (University of Pisa) (submittedVersion)
- Adelaide Research & Scholarship (AR&S) (University of Adelaide) (submittedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Florence Research (University of Florence) (submittedVersion)
- Institutional Research Information System (Università degli Studi di Brescia) (submittedVersion)
- Lund University Publications (Lund University) (submittedVersion)
- mediaTUM (Technical University of Munich) (submittedVersion)
- Open Repository and Bibliography (University of Luxembourg) (submittedVersion, cc-by-nc-sa)
- DZNE Pub (submittedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
- CINECA IRIS Institutional Research Information System (University of Bari Aldo Moro) (submittedVersion)
- UNSWorks (University of New South Wales, Sydney, Australia) (submittedVersion, cc-by-nc-nd)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Newcastle University ePrints (Newcastle Univesity)
- Funders
- ARUK (ARUK-PG2012-18)
- MRC Sudden Death Brain Bank (CS) (G0901254 to JH and MW)
- Fellowship award (G0802462 to MR)
- National Health and Medical Resarch Council (NHMRC), Australia (510217 and 1005769)
- NHMRC (630428 and 1005769, 510217 and 1005769, 1029538, 1037746)
- NHMRC Enabling (401184)
- NHMRC Research Fellowship 630434 (1029538, and Program Grant 1037746)
- NHMRC Career Development Fellowship 1022684 (1003139)
- NIH (P50 AG05681, P01 AG03991, and P01 AG026276, AG023501, AG019724)
- Fondazione CARIPLO (2009-2633, 2009–2633)
- CIHR (74580)
- PARF (C06-01)
- Newcastle Brain Tissue Resource (G0400074 and G1100540)
- BMBF (FKZ 01GI1007A)
- Cambridge NIHR Biomedical Research Centre and Wellcome Trust (088324)
- VMVD and JQT (AG032953, AG017586 and AG010124)
- MG (AG032953, AG017586, AG010124, and NS044266)
- German Ministry for Education and Research (01GS0465)
- MRC (G0301152)
- Motor Neuron Disease Association (6057)
- RR (P50 AG016574, R01 NS080882, R01 NS065782, P50 NS72187)
- DWD (P50NS072187, P50AG016574)
- State of Florida Alzheimer Disease Initiative, and CurePSP Inc. NRGR, JEP, RCP, DK, and BFB (P50 AG016574)
- KAJ (R01 AG037491)
- BLM (P50AG023501, P01AG019724)
- HR (AG032306)
- Stichting Dioraphte Foundation (11 02 03 00)
- Nuts Ohra Foundation (0801-69)
- Hersenstichting Nederland (BG 2010-02)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Clinical Neurology › Amyotrophic Lateral Sclerosis Research
- Keywords
- frontotemporal dementia, genetic susceptibility loci, semantic dementia, progressive nonfluent aphasia, HLA, 6p21.3, MAPT, gene regulatory networks, C9orf72, methylation quantitative trait loci
- MeSH terms
- Adult, Aged, Aged, 80 and over, Female, Genotype, Humans, Male, Middle Aged, Genome-Wide Association Study, Frontotemporal Dementia
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