Ferrari, Raffaele and Hernandez, Dena G. and Nalls, Michael A. and Rohrer, Jonathan D. and Ramasamy, Adaikalavan and Kwok, John B. J. and Dobson-Stone, Carol and Brooks, William S. and Schofield, Peter R. and Halliday, Glenda M. and Hodges, John R. and Piguet, Olivier and Bartley, Lauren and Thompson, Elizabeth and Haan, Eric and Hernandez, Isabel and Ruiz, Agustin and Boada, Merce and Borroni, Barbara and Padovani, Alessandro and Cruchaga, Carlos and Cairns, Nigel J. and Benussi, Luisa and Binetti, Giuliano and Ghidoni, Roberta and Forloni, Gianluigi and Galimberti, Daniela and Fenoglio, Chiara and Serpente, Maria and Scarpini, Elio and Clarimon, Jordi and Lleo, Alberto and Blesa, Rafael and Waldo, Maria Landqvist and Nilsson, Karin and Nilsson, Christer and Mackenzie, Ian R. A. and Hsiung, Ging-Yuek R. and Mann, David M. A. and Grafman, Jordan and Morris, Christopher M. and Attems, Johannes and Griffiths, Timothy D. and McKeith, Ian G. and Thomas, Alan J. and Pietrini, P. and Huey, Edward D. and Wassermann, Eric M. and Baborie, Atik and Jaros, Evelyn and Tierney, Michael C. and Pastor, Pau and Razquin, Cristina and Ortega-Cubero, Sara and Alonso, Elena and Perneczky, Robert and Diehl-Schmid, Janine and Alexopoulos, Panagiotis and Kurz, Alexander and Rainero, Innocenzo and Rubino, Elisa and Pinessi, Lorenzo and Rogaeva, Ekaterina and St George-Hyslop, Peter and Rossi, Giacomina and Tagliavini, Fabrizio and Giaccone, Giorgio and Rowe, James B. and Schlachetzki, Johannes C. M. and Uphill, James and Collinge, John and Mead, Simon and Danek, Adrian and Van Deerlin, Vivianna M. and Grossman, Murray and Trojanowski, John Q. and van der Zee, Julie and Deschamps, William and Van Langenhove, Tim and Cruts, Marc and Van Broeckhoven, Christine and Cappa, Stefano F. and Le Ber, Isabelle and Hannequin, Didier and Golfier, Veronique and Vercelletto, Martine and Brice, Alexis and Nacmias, Benedetta and Sorbi, Sandra and Bagnoli, Silvia and Piaceri, Irene and Nielsen, Jorgen E. and Hjermind, Lena E. and Riemenschneider, Matthias and Mayhaus, Manuel and Ibach, Bernd and Gasparoni, Gilles and Pichler, Sabrina and Gu, Wei and Rossor, Martin N. and Fox, Nick C. and Warren, Jason D. and Spillantini, Maria Grazia and Morris, Huw R. and Rizzu, Patrizia and Heutink, Peter and Snowden, Julie S. and Rollinson, Sara and Richardson, Anna and Gerhard, Alexander and Bruni, Amalia C. and Maletta, Raffaele and Frangipane, Francesca and Cupidi, Chiara and Bernardi, Livia and Anfossi, Maria and Gallo, Maura and Conidi, Maria Elena and Smirne, Nicoletta and Rademakers, Rosa and Baker, Matt and Dickson, Dennis W. and Graff-Radford, Neill R. and Petersen, Ronald C. and Knopman, David and Josephs, Keith A. and Boeve, Bradley F. and Parisi, Joseph E. and Seeley, William W. and Miller, Bruce L. and Karydas, Anna M. and Rosen, Howard and van Swieten, John C. and Dopper, Elise G. P. and Seelaar, Harro and Al Pijnenburg, Yolande and Scheltens, Philip and Logroscino, Giancarlo and Capozzo, Rosa and Novelli, Valeria and Puca, Annibale A. and Franceschi, Massimo and Postiglione, Alfredo and Milan, Graziella and Sorrentino, Paolo and Kristiansen, Mark and Chiang, Huei-Hsin and Graff, Caroline and Pasquier, Florence and Rollin, Adeline and Deramecourt, Vincent and Lebert, Florence and Kapogiannis, Dimitrios and Ferrucci, Luigi and Pickering-Brown, Stuart and Singleton, Andrew B. and Hardy, John and Momeni, Parastoo (2014) Frontotemporal dementia and its subtypes: a genome-wide association study. LANCET NEUROLOGY, 13 (7). pp. 686-699. ISSN 1474-4422, 1474-4465
Full text not available from this repository. (Request a copy)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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | AMYOTROPHIC-LATERAL-SCLEROSIS; LOBAR DEGENERATION; GENETIC-VARIATION; HEXANUCLEOTIDE REPEAT; SUSCEPTIBILITY LOCI; DIAGNOSTIC-CRITERIA; PARKINSONS-DISEASE; MULTIPLE-SCLEROSIS; ALZHEIMER-DISEASE; COMMON VARIANTS; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Psychiatrie und Psychotherapie |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 16 Sep 2019 10:50 |
| Last Modified: | 16 Sep 2019 10:50 |
| URI: | https://pred.uni-regensburg.de/id/eprint/9965 |
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