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., Brooks 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 - Funding Information:
CVB and MC are inventors on patent applications for GRN and C9orf72. PRS receives speaker fees from Janssen pharmaceutical. RR receives research support from the NIH ( R01 NS080882, R01 NS065782, R01 AG026251, R01 NS076471, and P50 AG16574 ), the ALS Therapy Alliance, and the Consortium for Frontotemporal Degeneration Research, honoraria for lectures or educational activities not funded by industry. RR serves on the medical advisory board of the Association for Frontotemporal Degeneration and the board of directors of the International Society for Frontotemporal Dementia, and holds a patent on methods to screen for the hexanucleotide repeat expansion in the C9ORF72 gene. DWD is supported by NIH grants ( P50 AG16574, P50 NS72187, P01 AG03949 ), the Mangurian Foundation, CurePSP, and the Robert E Jacoby Professorship for Alzheimer's Research. NRGR is on the Scientific Advisory Board for Codman, TauRzx multicenter study, Consultation for CYTOX. RCP chairs a Data Monitoring Committee for Pfizer and Janssen Alzheimer Immunotherapy, and is a consultant for GE Healthcare and Elan Pharmaceuticals. RCP receives royalties from Oxford University Press for Mild Cognitive Impairment. DK has served on a data safety monitoring board for Lilly Pharmaceuticals, as a consultant to TauRx, was an investigator in clinical trials sponsored by Baxter, Elan Pharmaceuticals, and Forest Pharmaceuticals in the past 2 years and receives research support from the NIH. BFB has served as an investigator for clinical trials sponsored by Cephalon Inc, Allon Pharmaceuticals, and GE Healthcare. BFB receives royalties from the publication of a book entitled Behavioral Neurology Of Dementia (Cambridge Medicine, 2009). BFB has received honoraria from the American Academy of Neurology. BFB serves on the Scientific Advisory Board of the Tau Consortium. BFB receives research support from the National Institute on Aging ( P50 AG016574, U01 AG006786, RO1 AG032306, RO1 AG041797 ) and the Mangurian Foundation. BLM is on the Board Membership of The Larry L Hillblom Foundation, The John Douglas French Foundation, The Tau Consortium, Sagol School of Neuroscience Tel Aviv University. BLM holds consultancy for Tau Rx lts—Chair, Scientific Advisory Board bvFTD Trial Allon Therapeutics—Steering Committee AL-108-231 Study, Bristol-Myers Squibb-Advisory Board, Progressive Supranuclear Palsy (PSP), Neurology Scientific Advisory Board Meeting Siemens Molecular Imaging, and Eli Lilly US Alzheimer's Disease Advisory Board, and receives royalties from Cambridge University Press Guilford Publications Inc, Neurocase. RF, DGH, MAN, JDR, AR, JBJK, CDS, WSB, GMH, JRH, OP, LB, ET, EH, IH, AR, MB, BB, AP, CC, NJC, LB, GB, RG, GF, DG, CF, MS, ES, JC, AL, RB, MLW, KN, CN, IRAM, G-YRH, DMAM, JG, CMM, JA, TDG, IGM, AJT, PP, EDH, EMW, AB, EJ, MCT, PP, CR, SO-C, EA, RP, JDS, PA, AK, IR, ER, LP, ER, PStG-H, GR, FT, GG, JBR, JCMS, JU, JC, SM, AD, VMVD, MG, JQT, JvdZ, WD, TVL, SFC, ILB, DH, VG, MV, AB, BN, SS, SB, IP, JEN, LEH, MR, MM, BI, GG, SP, WG, MNR, NCF, JDW, MGS, HRM, PR, PH, JSS, SR, AR, AG, ACB, RM, FF, CC, LB, MA, MG, MEC, NS, MB, KAJ, JEP, WWS, AMK, HR, JCvS, EGPD, HS, YALP, PS, GL, RC, VN, AAP, MF, AP, GM, PS, MK, H-HC, CG, FP, AR, VD, FL, DK, LF, SPB, JH, PM, and ABS declare no competing interests.
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.
UR - http://www.scopus.com/inward/record.url?scp=84902509590&partnerID=8YFLogxK
U2 - 10.1016/S1474-4422(14)70065-1
DO - 10.1016/S1474-4422(14)70065-1
M3 - Article
C2 - 24943344
AN - SCOPUS:84902509590
SN - 1474-4422
VL - 13
SP - 686
EP - 699
JO - The Lancet Neurology
JF - The Lancet Neurology
IS - 7
ER -