TY  - JOUR
VL  - 13
EP  -  699
ID  - eprints2875
N2  - SummaryBackground 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.
SP  - 686 
A1  - Ferrari, Raffaele
A1  - Hernandez, Dena G
A1  - Nalls, Michael A
A1  - Rohrer, Jonathan D
A1  - Ramasamy, Adaikalavan
A1  - Kwok, John B J
A1  - Dobson-Stone, Carol
A1  - Brooks, William S
A1  - Schofield, Peter R
A1  - Halliday, Glenda M
A1  - Hodges, John R
A1  - Piguet, Olivier
A1  - Bartley, Lauren
A1  - Thompson, Elizabeth
A1  - Haan, Eric
A1  - Hernández, Isabel
A1  - Ruiz, Agustín
A1  - Boada, Mercè
A1  - Borroni, Barbara
A1  - Padovani, Alessandro
A1  - Cruchaga, Carlos
A1  - Cairns, Nigel J
A1  - Benussi, Luisa
A1  - Binetti, Giuliano
A1  - Ghidoni, Roberta
A1  - Forloni, Gianluigi
A1  - Galimberti, Daniela
A1  - Fenoglio, Chiara
A1  - Serpente, Maria
A1  - Scarpini, Elio
A1  - Clarimón, Jordi
A1  - Lleó, Alberto
A1  - Blesa, Rafael
A1  - Waldö, Maria Landqvist
A1  - Nilsson, Karin
A1  - Nilsson, Christer
A1  - Mackenzie, Ian R A
A1  - Hsiung, Ging-Yuek R
A1  - Mann, David M A
A1  - Grafman, Jordan
A1  - Morris, Christopher M
A1  - Attems, Johannes
A1  - Griffiths, Timothy D
A1  - McKeith, Ian G
A1  - Thomas, Alan J
A1  - Pietrini, Pietro
A1  - Huey, Edward D
A1  - Wassermann, Eric M.
A1  - Baborie, Atik
A1  - Jaros, Evelyn
A1  - Tierney, Michael C.
A1  - Pastor, Pau
A1  - Razquin, Cristina
A1  - Ortega-Cubero, Sara
A1  - Alonso, Elena
A1  - Perneczky, Robert
A1  - Diehl-Schmid, Janine
A1  - Alexopoulos, Panagiotis
A1  - Kurz, Alexander
A1  - Rainero, Innocenzo
A1  - Rubino, Elisa
A1  - Pinessi, Lorenzo
A1  - Rogaeva, Ekaterina
A1  - George-Hyslop, Peter St
A1  - Rossi, Giacomina
A1  - Tagliavini, Fabrizio
A1  - Giaccone, Giorgio
A1  - Rowe, James B
A1  - Schlachetzki, Johannes C M
A1  - Uphill, James
A1  - Collinge, John
A1  - Mead, Simon
A1  - Danek, Adrian
A1  - Deerlin, Vivianna M Van
A1  - Grossman, Murray
A1  - Trojanowski, John Q
A1  - van der Zee, Julie
A1  - Deschamps, William
A1  - Langenhove, Tim Van
A1  - Cruts, Marc
A1  - Broeckhoven, Christine Van
A1  - Cappa, Stefano F
A1  - Ber, Isabelle Le
A1  - Hannequin, Didier
A1  - Golfier, Véronique
A1  - Vercelletto, Martine
A1  - Brice, Alexis
A1  - Nacmias, Benedetta
A1  - Sorbi, Sandro
A1  - Bagnoli, Silvia
A1  - Piaceri, Irene
A1  - Nielsen, Jørgen E
A1  - Hjermind, Lena E
A1  - Riemenschneider, Matthias
A1  - Mayhaus, Manuel
A1  - Ibach, Bernd
A1  - Gasparoni, Gilles
A1  - Pichler, Sabrina
A1  - Gu, Wei
A1  - Rossor, Martin N
A1  - Fox, Nick C
A1  - Warren, Jason D
A1  - Spillantini, Maria Grazia
A1  - Morris, Huw R
A1  - Rizzu, Patrizia
A1  - Heutink, Peter
A1  - Snowden, Julie S
A1  - Rollinson, Sara
A1  - Richardson, Anna
A1  - Gerhard, Alexander
A1  - Bruni, Amalia C
A1  - Maletta, Raffaele
A1  - Frangipane, Francesca
A1  - Cupidi, Chiara
A1  - Bernardi, Livia
A1  - Anfossi, Maria
A1  - Gallo, Maura
A1  - Conidi, Maria Elena
A1  - Smirne, Nicoletta
A1  - Rademakers, Rosa
A1  - Baker, Matt
A1  - Dickson, Dennis W
A1  - Graff-Radford, Neill R.
A1  - Petersen, Ronald C
A1  - Knopman, David
A1  - Josephs, Keith A
A1  - Boeve, Bradley F
A1  - Parisi, Joseph E
A1  - Seeley, William W
A1  - Miller, Bruce L
A1  - Karydas, Anna M
A1  - Rosen, Howard
A1  - van Swieten, John C
A1  - Dopper, Elise G P
A1  - Seelaar, Harro
A1  - Pijnenburg, Yolande A L
A1  - Scheltens, Philip
A1  - Logroscino, Giancarlo
A1  - Capozzo, Rosa
A1  - Novelli, Valeria
A1  - Puca, Annibale A
A1  - Franceschi, Massimo
A1  - Postiglione, Alfredo
A1  - Milan, Graziella
A1  - Sorrentino, Paolo
A1  - Kristiansen, Mark
A1  - Chiang, Huei-Hsin
A1  - Graff, Caroline
A1  - Pasquier, Florence
A1  - Rollin, Adeline
A1  - Deramecourt, Vincent
A1  - Lebert, Florence
A1  - Kapogiannis, Dimitrios
A1  - Ferrucci, Luigi
A1  - Pickering-Brown, Stuart
A1  - Singleton, Andrew B
A1  - Hardy, John
A1  - Momeni, Parastoo
SN  - 1474-4422
PB  - Elsevier
UR  - http://www.sciencedirect.com/science/article/pii/S1474442214700651
IS  - 7
JF  - The Lancet Neurology
AV  - public
TI  - Frontotemporal dementia and its subtypes: a genome-wide association study
Y1  - 2014///
ER  -