Journal
LANCET NEUROLOGY
Volume 13, Issue 7, Pages 686-699Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/S1474-4422(14)70065-1
Keywords
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Categories
Funding
- National Institute of Neurological Disorders and Stroke (NINDS)
- National Institute on Aging (NIA)
- Wellcome/MRC Centre on Parkinson's disease
- Alzheimer's Research UK (ARUK) [ARUK-PG2012-18]
- office of the Dean of the School of Medicine, Department of Internal Medicine, at Texas Tech University Health Sciences Center
- Intramural Research Program of the National Institute on Aging, National Institutes of Health, part of the US Department of Health and Human Services [ZIA AG000932-04]
- Department of Defense [W81XWH-09-2-0128]
- MRC through the MRC Sudden Death Brain Bank
- King Faisal Specialist Hospital and Research Centre, Saudi Arabia
- National Health and Medical Resarch Council (NHMRC), Australia [510217, 1005769]
- NHMRC [510217, 1005769, 630428]
- NHMRC Enabling Grant [401184]
- NHMRC Research Fellowship [630434, 1029538, 1037746]
- Australian Research Council Federation Fellowship
- NHMRC Project Grant [1029538]
- NHMRC Program Grant [1037746]
- NHMRC Career Development Fellowship [1022684, 1003139]
- Ricerca Corrente, Italian Ministry of Health
- Fondazione CARIPLO, Ricerca Corrente, Italian Ministry of Health [2009-2633]
- Fondazione CARIPLO [2009-2633]
- Italian Ministry of Health
- Fondazione Cariplo
- Italian Ministry of Health (Ricerca Corrente)
- Government funding of clinical research within NHS Sweden (ALF)
- Thure Carlsson Foundation
- Swedish Alzheimer Fund
- CIHR [74580]
- PARF [C06-01]
- NINDS intramural research funds for FTD research
- Medical Research Council UK
- Brains for Dementia Research
- Alzheimer's Society
- Alzheimer's Research UK
- National Institutes for Health Research
- Department of Health
- Yvonne Mairy Bequest
- UK MRC [G0400074, G1100540]
- Alzheimer's Research Trust
- Alzheimer's Society through the Brains for Dementia Research Initiative
- NIHR Biomedical Research Centre Grant in Ageing and Health
- NIHR Biomedical Research Unit in Lewy Body Disorders
- UK Department of Health
- Medical Research Council
- National Institute for Health Research Newcastle Biomedical Research Centre based at Newcastle Hospitals Foundation Trust
- Newcastle University
- MRC
- Dunhill Medical Trust
- NIHR Biomedical Research Centre and Unit on Ageing Grants
- NIHR
- Newcastle Biomedical Research Centre
- FIMA (Foundation for Applied Medical Research)
- German Federal Ministry of Education and Research (BMBF-German FTLD consortium) [FKZ 01GI1007A]
- Ministero dell'Istruzione, dell'Universita e della Ricerca (MIUR) of Italy
- Canadian Institutes of Health Research
- Wellcome Trust
- Ontario Research Fund
- MIUR grant [RBAP11FRE9]
- Cambridge NIHR Biomedical Research Centre
- Wellcome Trust [088324]
- MRC Prion Unit core Binding
- MetLife Foundation Award for Medical Research
- Belgian Science Policy Office Interuniversity Attraction Poles programme
- Foundation for Alzheimer Research (SAO-FRA)
- Medical Foundation Queen Elisabeth
- Flemish Government Methusalem Excellence award
- Research Foundation Flanders (FWO)
- University of Antwerp Research Fund
- FWO
- programme Investissements d'avenir [ANR-10-IAIHU-06]
- Cassa di Rispario di Firenze e Cassa di Risparmio di Pistoia e Pescia
- Novo Nordisk Foundation, Denmark
- German National Genome Network (NGFN)
- German Ministry for Education and Research Grant [01GS0465]
- MRC programme grant
- NIHR Queen Square Dementia Biomedical Research Unit
- Leonard Wolfson Experimental Neurology Centre
- MRC grant [G0301152]
- Cambridge Biomedical Research Centre
- Motor Neuron Disease Association [6057]
- Consortium for Frontotemporal Dementia
- State of Florida Alzheimer Disease Initiative
- CurePSP Inc.
- NIH, Consortium for Frontotemporal Dementia Research [AG023501, AG019724]
- Consortium for FTD Research [P50AG023501, P01AG019724]
- Stichting Dioraphte Foundation [11 02 03 00]
- Nuts Ohra Foundation [0801-69]
- Hersenstichting Nederland [BG 2010-02]
- Alzheimer Nederland
- Swedish Brain Power (SBP)
- Strategic Research Programme in Neuroscience at Karolinska Institutet (StratNeuro)
- Stockholm County Council
- Karolinska Institutet
- Swedish Alzheimer Foundation
- Swedish Research Council
- Karolinska Institutet PhD-student funding
- King Gustaf V, and Queen Victoria's Free Mason Foundation
- [G0901254]
- [G0802462]
- [P30-NS069329-01]
- [AG032953]
- [AG017586]
- [AG010124]
- [NS044266]
- [Prin 2010-prot.2010PWNJXK]
- [P50 AG016574]
- [R01 NS080882]
- [R01 NS065782]
- [P50 NS72187]
- [P50NS072187]
- [P50AG016574]
- [R01 AG037491]
- [AG032306]
- Alzheimers Research UK [ART-PG2011-20, ARUK-PG2012-18] Funding Source: researchfish
- Medical Research Council [G0900652, G0802462, MC_U123192748, MR/J009482/1, G0301152, MR/L016451/1, G0502157, MR/K006584/1, G1100643, G0400074, G0701441, G1100540, G0901254, G0700943, MC_U123160651, MC_U105597119] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0508-10123, CL-2012-18-010, NF-SI-0513-10134, ACF-2007-18-011, NF-SI-0611-10048, NF-SI-0512-10033] Funding Source: researchfish
- Novo Nordisk Fonden [NNF11OC1014514] Funding Source: researchfish
- MRC [G0301152, G0802462, MR/J009482/1, G0900652, G0701441, G0400074, G1100643, G1100540, MC_U123192748, MC_U105597119, MC_U123160651, G0901254, G0700943, MR/L016451/1, G0502157] Funding Source: UKRI
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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.
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