Article (Scientific journals)
Frontotemporal dementia and its subtypes: a genome-wide association study.
Ferrari, Raffaele; Hernandez, Dena G.; Nalls, Michael A. et al.
2014In The Lancet Neurology, 13 (7), p. 686-99
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Abstract :
[en] 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 x 10(-8)) single-nucleotide polymorphisms. FINDINGS: We identified novel associations exceeding the genome-wide significance threshold (p<5 x 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 x 10(-8); odds ratio=1.204 [95% CI 1.11-1.30]), rs9268856 (p=5.51 x 10(-9); 0.809 [0.76-0.86]) and rs1980493 (p value=1.57 x 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 x 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.
Research center :
- Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group)
Disciplines :
Neurology
Author, co-author :
Ferrari, Raffaele
Hernandez, Dena G.
Nalls, Michael A.
Rohrer, Jonathan D.
Ramasamy, Adaikalavan
Kwok, John B. J.
Dobson-Stone, Carol
Brooks, William S.
Schofield, Peter R.
Halliday, Glenda M.
Hodges, John R.
Piguet, Olivier
Bartley, Lauren
Thompson, Elizabeth
Haan, Eric
Hernandez, Isabel
Ruiz, Agustin
Boada, Merce
Borroni, Barbara
Padovani, Alessandro
Cruchaga, Carlos
Cairns, Nigel J.
Benussi, Luisa
Binetti, Giuliano
Ghidoni, Roberta
Forloni, Gianluigi
Galimberti, Daniela
Fenoglio, Chiara
Serpente, Maria
Scarpini, Elio
Clarimon, Jordi
Lleo, Alberto
Blesa, Rafael
Waldo, 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.
Baborie, Atik
Jaros, Evelyn
Tierney, Michael C.
Pastor, Pau
Razquin, Cristina
Ortega-Cubero, Sara
Alonso, Elena
Perneczky, Robert
Diehl-Schmid, Janine
Alexopoulos, Panagiotis
Kurz, Alexander
Rainero, Innocenzo
Rubino, Elisa
Pinessi, Lorenzo
Rogaeva, Ekaterina
St George-Hyslop, Peter
Rossi, Giacomina
Tagliavini, Fabrizio
Giaccone, Giorgio
Rowe, James B.
Schlachetzki, Johannes C. M.
Uphill, James
Collinge, John
Mead, Simon
Danek, Adrian
Van Deerlin, Vivianna M.
Grossman, Murray
Trojanowski, John Q.
van der Zee, Julie
Deschamps, William
Van Langenhove, Tim
Cruts, Marc
Van Broeckhoven, Christine
Cappa, Stefano F.
Le Ber, Isabelle
Hannequin, Didier
Golfier, Veronique
Vercelletto, Martine
Brice, Alexis
Nacmias, Benedetta
Sorbi, Sandro
Bagnoli, Silvia
Piaceri, Irene
Nielsen, Jorgen E.
Hjermind, Lena E.
Riemenschneider, Matthias
Mayhaus, Manuel
Ibach, Bernd
Gasparoni, Gilles
Pichler, Sabrina
Gu, Wei ;  University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB)
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
Frangipane, Francesca
Cupidi, Chiara
Bernardi, Livia
Anfossi, Maria
Gallo, Maura
Conidi, Maria Elena
Smirne, Nicoletta
Rademakers, Rosa
Baker, Matt
Dickson, Dennis W.
Graff-Radford, Neill R.
Petersen, Ronald C.
Knopman, David
Josephs, Keith A.
Boeve, Bradley F.
Parisi, Joseph E.
Seeley, William W.
Miller, Bruce L.
Karydas, Anna M.
Rosen, Howard
van Swieten, John C.
Dopper, Elise G. P.
Seelaar, Harro
Pijnenburg, Yolande A. L.
Scheltens, Philip
Logroscino, Giancarlo
Capozzo, Rosa
Novelli, Valeria
Puca, Annibale A.
Franceschi, Massimo
Postiglione, Alfredo
Milan, Graziella
Sorrentino, Paolo
Kristiansen, Mark
Chiang, Huei-Hsin
Graff, Caroline
Pasquier, Florence
Rollin, Adeline
Deramecourt, Vincent
Lebert, Florence
Kapogiannis, Dimitrios
Ferrucci, Luigi
Pickering-Brown, Stuart
Singleton, Andrew B.
Hardy, John
Momeni, Parastoo
More authors (148 more) Less
Language :
English
Title :
Frontotemporal dementia and its subtypes: a genome-wide association study.
Publication date :
2014
Journal title :
The Lancet Neurology
ISSN :
1474-4422
eISSN :
1474-4465
Publisher :
The Lancet Publishing Group, United Kingdom
Volume :
13
Issue :
7
Pages :
686-99
Peer reviewed :
Peer Reviewed verified by ORBi
Commentary :
Copyright (c) 2014 Elsevier Ltd. All rights reserved.
Available on ORBilu :
since 23 June 2014

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