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Frontotemporal dementia and its subtypes: a genome-wide association study

Lookup NU author(s): Dr Christopher Morris, Professor Johannes Attems, Professor Tim GriffithsORCiD, Professor Ian McKeith, Professor Alan ThomasORCiD

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Abstract

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.


Publication metadata

Author(s): Ferrari R, Hernandez DG, Nalls MA, Rohrer JD, Ramasamy A, Kwok JBJ, Dobson-Stone C, Brooks WS, Schofield PR, Halliday GM, Hodges JR, Piguet O, Bartley L, Thompson E, Haan E, Hernandez I, Ruiz A, Boada M, Borroni B, Padovani A, Cruchaga C, Cairns NJ, Benussi L, Binetti G, Ghidoni R, Forloni G, Galimberti D, Fenoglio C, Serpente M, Scarpini E, Clarimon J, Lleo A, Blesa R, Waldo ML, Nilsson K, Nilsson C, Mackenzie IRA, Hsiung GYR, Mann DMA, Grafman J, Morris CM, Attems J, Griffiths TD, McKeith IG, Thomas AJ, Pietrini P, Huey ED, Wassermann EM, Baborie A, Jaros E, Tierney MC, 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 JB, Schlachetzki JCM, Uphill J, Collinge J, Mead S, Danek A, Van Deerlin VM, Grossman M, Trojanowski JQ, van der Zee J, Deschamps W, Van Langenhove T, Cruts M, Van Broeckhoven C, Cappa SF, Le Ber I, Hannequin D, Golfier V, Vercelletto M, Brice A, Nacmias B, Sorbi S, Bagnoli S, Piaceri I, Nielsen JE, Hjermind LE, Riemenschneider M, Mayhaus M, Ibach B, Gasparoni G, Pichler S, Gu W, Rossor MN, Fox NC, Warren JD, Spillantini MG, Morris HR, Rizzu P, Heutink P, Snowden JS, Rollinson S, Richardson A, Gerhard A, Bruni AC, Maletta R, Frangipane F, Cupidi C, Bernardi L, Anfossi M, Gallo M, Conidi ME, Smirne N, Rademakers R, Baker M, Dickson DW, Graff-Radford NR, Petersen RC, Knopman D, Josephs KA, Boeve BF, Parisi JE, Seeley WW, Miller BL, Karydas AM, Rosen H, van Swieten JC, Dopper EGP, Seelaar H, Al Pijnenburg Y, Scheltens P, Logroscino G, Capozzo R, Novelli V, Puca AA, Franceschi M, Postiglione A, Milan G, Sorrentino P, Kristiansen M, Chiang HH, Graff C, Pasquier F, Rollin A, Deramecourt V, Lebert F, Kapogiannis D, Ferrucci L, Pickering-Brown S, Singleton AB, Hardy J, Momeni P

Publication type: Article

Publication status: Published

Journal: Lancet Neurology

Year: 2014

Volume: 13

Issue: 7

Pages: 686-699

Print publication date: 01/07/2014

ISSN (print): 1474-4422

ISSN (electronic): 1474-4465

Publisher: Lancet Publishing Group

URL: http://dx.doi.org/10.1016/S1474-4422(14)70065-1

DOI: 10.1016/S1474-4422(14)70065-1


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Funding

Funder referenceFunder name
Alzheimer's Research Trust
Alzheimer's Research UK
Belgian Science Policy Office Interuniversity Attraction Poles programme
Cambridge NIHR Biomedical Research Centre
Cassa di Rispario di Firenze e Cassa di Risparmio di Pistoia e Pescia
Department of Health
FIMA (Foundation for Applied Medical Research)
Flemish Government Methusalem Excellence award
Fondazione Cariplo
FWO
German National Genome Network (NGFN)
Government funding of clinical research within NHS Sweden (ALF)
Karolinska Institutet
King Faisal Specialist Hospital and Research Centre, Saudi Arabia
Medical Foundation Queen Elisabeth
Medical Research Council
Medical Research Council UK
MetLife Foundation Award for Medical Research
Ministero dell'Istruzione, dell'Universita e della Ricerca (MIUR) of Italy
MRC
MRC Prion Unit core Binding
MRC through the MRC Sudden Death Brain Bank
National Institute for Health Research Newcastle Biomedical Research Centre based at Newcastle Hospitals Foundation Trust
National Institute of Neurological Disorders and Stroke (NINDS)
National Institutes for Health Research
Newcastle Biomedical Research Centre
Newcastle University
NIHR Biomedical Research Centre Grant in Ageing and Health
Novo Nordisk Foundation, Denmark
Ontario Research Fund
State of Florida Alzheimer Disease Initiative
Stockholm County Council
Swedish Research Council
Thure Carlsson Foundation
University of Antwerp Research Fund
Alzheimer Nederland
Alzheimer's Society
Alzheimer's Society through the Brains for Dementia Research Initiative
Australian Research Council Federation Fellowship
Brains for Dementia Research
Cambridge Biomedical Research Centre
Canadian Institutes of Health Research
Consortium for Frontotemporal Dementia
CurePSP Inc.
Dunhill Medical Trust
Foundation for Alzheimer Research (SAO-FRA)
Italian Ministry of Health
Italian Ministry of Health (Ricerca Corrente)
Karolinska Institutet PhD-student funding
King Gustaf V, and Queen Victoria's Free Mason Foundation
Leonard Wolfson Experimental Neurology Centre
MRC programme grant
National Institute on Aging (NIA)
NIHR
NIHR Biomedical Research Centre and Unit on Ageing Grants
NIHR Biomedical Research Unit in Lewy Body Disorders
NIHR Queen Square Dementia Biomedical Research Unit
NINDS intramural research funds for FTD research
office of the Dean of the School of Medicine, Department of Internal Medicine, at Texas Tech University Health Sciences Center
Research Foundation Flanders (FWO)
Ricerca Corrente, Italian Ministry of Health
Strategic Research Programme in Neuroscience at Karolinska Institutet (StratNeuro)
Swedish Alzheimer Foundation
Swedish Alzheimer Fund
Swedish Brain Power (SBP)
UK Department of Health
Wellcome Trust
Wellcome/MRC Centre on Parkinson's disease
Yvonne Mairy Bequest
01GS0465German Ministry for Education and Research Grant
088324Wellcome Trust
1003139NHMRC Career Development Fellowship
1022684NHMRC Career Development Fellowship
0801-69Nuts Ohra Foundation
1005769National Health and Medical Resarch Council (NHMRC), Australia
1005769NHMRC
1029538NHMRC Project Grant
1029538NHMRC Research Fellowship
1037746NHMRC Program Grant
1037746NHMRC Research Fellowship
11 02 03 00Stichting Dioraphte Foundation
401184NHMRC Enabling Grant
2009-2633Fondazione CARIPLO
2009-2633Fondazione CARIPLO, Ricerca Corrente, Italian Ministry of Health
630434NHMRC Research Fellowship
AG010124
AG019724NIH, Consortium for Frontotemporal Dementia Research
AG032306
AG032953
ANR-10-IAIHU-06programme Investissements d'avenir
ARUK-PG2012-18Alzheimer's Research UK (ARUK)
510217National Health and Medical Resarch Council (NHMRC), Australia
510217NHMRC
6057Motor Neuron Disease Association
630428NHMRC
74580CIHR
BG 2010-02Hersenstichting Nederland
C06-01PARF
AG017586
AG023501NIH, Consortium for Frontotemporal Dementia Research
FKZ 01GI1007AGerman Federal Ministry of Education and Research (BMBF-German FTLD consortium)
G0400074UK MRC
G0301152MRC grant
G0802462
G0901254
G1100540UK MRC
NS044266
P01AG019724Consortium for FTD Research
P30-NS069329-01
P50 AG016574
P50 NS72187
P50AG023501Consortium for FTD Research
R01 NS065782
P50AG016574
P50NS072187
RBAP11FRE9MIUR grant
Prin 2010-prot.2010PWNJXK
R01 AG037491
R01 NS080882
W81XWH-09-2-0128Department of Defense
ZIA AG000932-04Intramural Research Program of the National Institute on Aging, National Institutes of Health, part of the US Department of Health and Human Services

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