TY - JOUR

T1 - Frontotemporal dementia and its subtypes

T2 - a genome-wide association study

AU - Ferrari, Raffaele

AU - Hernandez, Dena G

AU - Nalls, Michael A

AU - Rohrer, Jonathan D

AU - Ramasamy, Adaikalavan

AU - Kwok, John B J

AU - Dobson-Stone, Carol

AU - Brooks, William S

AU - Schofield, Peter R

AU - Halliday, Glenda M

AU - Hodges, John R

AU - Piguet, Olivier

AU - Bartley, Lauren

AU - Thompson, Elizabeth

AU - Haan, Eric

AU - Hernández, Isabel

AU - Ruiz, Agustín

AU - Boada, Mercè

AU - Borroni, Barbara

AU - Padovani, Alessandro

AU - Cruchaga, Carlos

AU - Cairns, Nigel J

AU - Benussi, Luisa

AU - Binetti, Giuliano

AU - Ghidoni, Roberta

AU - Forloni, Gianluigi

AU - Galimberti, Daniela

AU - Fenoglio, Chiara

AU - Serpente, Maria

AU - Scarpini, Elio

AU - Clarimón, Jordi

AU - Lleó, Alberto

AU - Blesa, Rafael

AU - Waldö, Maria Landqvist

AU - Nilsson, Karin

AU - Nilsson, Christer

AU - Mackenzie, Ian R A

AU - Hsiung, Ging-Yuek R

AU - Mann, David M A

AU - Grafman, Jordan

AU - Morris, Christopher M

AU - Attems, Johannes

AU - Griffiths, Timothy D

AU - McKeith, Ian G

AU - Thomas, Alan J

AU - Pietrini, P

AU - Huey, Edward D

AU - Wassermann, Eric M

AU - Baborie, Atik

AU - Jaros, Evelyn

AU - Tierney, Michael C

AU - Pastor, Pau

AU - Razquin, Cristina

AU - Ortega-Cubero, Sara

AU - Alonso, Elena

AU - Perneczky, Robert

AU - Diehl-Schmid, Janine

AU - Alexopoulos, Panagiotis

AU - Kurz, Alexander

AU - Rainero, Innocenzo

AU - Rubino, Elisa

AU - Pinessi, Lorenzo

AU - Rogaeva, Ekaterina

AU - St George-Hyslop, Peter

AU - Rossi, Giacomina

AU - Tagliavini, Fabrizio

AU - Giaccone, Giorgio

AU - Rowe, James B

AU - Schlachetzki, Johannes C M

AU - Uphill, James

AU - Collinge, John

AU - Mead, Simon

AU - Danek, Adrian

AU - Van Deerlin, Vivianna M

AU - Grossman, Murray

AU - Trojanowski, John Q

AU - van der Zee, Julie

AU - Deschamps, William

AU - Van Langenhove, Tim

AU - Cruts, Marc

AU - Van Broeckhoven, Christine

AU - Cappa, Stefano F

AU - Le Ber, Isabelle

AU - Hannequin, Didier

AU - Golfier, Véronique

AU - Vercelletto, Martine

AU - Brice, Alexis

AU - Nacmias, Benedetta

AU - Sorbi, Sandro

AU - Bagnoli, Silvia

AU - Piaceri, Irene

AU - Nielsen, Jørgen E

AU - Hjermind, Lena E

AU - Riemenschneider, Matthias

AU - Mayhaus, Manuel

AU - Ibach, Bernd

AU - Gasparoni, Gilles

AU - Pichler, Sabrina

AU - Gu, Wei

AU - Rossor, Martin N

AU - Fox, Nick C

AU - Warren, Jason D

AU - Spillantini, Maria Grazia

AU - Morris, Huw R

AU - Rizzu, Patrizia

AU - Heutink, Peter

AU - Snowden, Julie S

AU - Rollinson, Sara

AU - Richardson, Anna

AU - Gerhard, Alexander

AU - Bruni, Amalia C

AU - Maletta, Raffaele

AU - Frangipane, Francesca

AU - Cupidi, Chiara

AU - Bernardi, Livia

AU - Anfossi, Maria

AU - Gallo, Maura

AU - Conidi, Maria Elena

AU - Smirne, Nicoletta

AU - Rademakers, Rosa

AU - Baker, Matt

AU - Dickson, Dennis W

AU - Graff-Radford, Neill R

AU - Petersen, Ronald C

AU - Knopman, David

AU - Josephs, Keith A

AU - Boeve, Bradley F

AU - Parisi, Joseph E

AU - Seeley, William W

AU - Miller, Bruce L

AU - Karydas, Anna M

AU - Rosen, Howard

AU - van Swieten, John C

AU - Dopper, Elise G P

AU - Seelaar, Harro

AU - Pijnenburg, Yolande A L

AU - Scheltens, Philip

AU - Logroscino, Giancarlo

AU - Capozzo, Rosa

AU - Novelli, Valeria

AU - Puca, Annibale A

AU - Franceschi, Massimo

AU - Postiglione, Alfredo

AU - Milan, Graziella

AU - Sorrentino, Paolo

AU - Kristiansen, Mark

AU - Chiang, Huei-Hsin

AU - Graff, Caroline

AU - Pasquier, Florence

AU - Rollin, Adeline

AU - Deramecourt, Vincent

AU - Lebert, Florence

AU - Kapogiannis, Dimitrios

AU - Ferrucci, Luigi

AU - Pickering-Brown, Stuart

AU - Singleton, Andrew B

AU - Hardy, John

AU - Momeni, Parastoo

N1 - Copyright © 2014 Elsevier Ltd. All rights reserved.

PY - 2014/7

Y1 - 2014/7

N2 - 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.

AB - 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.

U2 - 10.1016/S1474-4422(14)70065-1

DO - 10.1016/S1474-4422(14)70065-1

M3 - Journal article

C2 - 24943344

VL - 13

SP - 686

EP - 699

JO - The Lancet Neurology

JF - The Lancet Neurology

SN - 1474-4422

IS - 7

ER -