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

Raffaele Ferrari, Dena Hernandez, Michael Nalls, Jonathan Rohrer, Adaikalavan Ramasamy, John Kwok, Carol Dobson-Stone, William Brooks, Peter Schofield, Glenda Halliday, John Hodges, Olivier Piguet, Lauren Bartley, Elizabeth Thompson, Eric Haan, Isabel Hernandez, Agustin Ruiz, Merce Boada, Barbara Borroni, Alessandro PadovaniCarlos Cruchaga, Nigel Cairns, L Benussi, Giuliano Binetti, Roberta Ghidoni, Gianluigi Forloni, Daniela Galimberti, Chiara Fenoglio, Maria Serpente, Elio Scarpini, Jordi Clarimon, Alberto Lleo, Rafael Blesa, Maria Waldo, K Nilsson, Christer Nilsson, Ian Mackenzie, Ging-Yuek Hsiung, David Mann, Jordan Grafman, Christopher Morris, Johannes Attems, Timothy Griffiths, Ian McKeith, Alan Thomas, P Pietrini, Edward Huey, Eric Wassermann, Atik Baborie, Evelyn Jaros, Michael Tierney, Pau Pastor, Cristina Razquin, Sara Ortega-Cubero, Elena Alonso, Robert Perneczky, Janine Diehl-Schmid, Panagiotis Alexopoulos, Alexander Kurz, Innocenzo Rainero, Elisa Rubino, Lorenzo Pinessi, Ekaterina Rogaeva, Peter St George-Hyslop, Giacomina Rossi, Fabrizio Tagliavini, Giorgio Giaccone, James Rowe, Johannes Schlachetzki, James Uphill, John Collinge, Simon Mead, Adrian Danek, Vivianna van Deerlin, Murray Grossman, John Trojanowski, Julie van der Zee, William Deschamps, Tim Van Langenhove, Marc Cruts, Christine Van Broeckhoven, Stefano Cappa, Isabelle Le Ber, Didier Hannequin, Veronique Golfier, Martine Vercelletto, Alexis Brice, Benedetta Nacmias, Sandro Sorbi, Silvia Bagnoli, Irene Piaceri, Jorgen Nielsen, Lena Hjermind, Matthias Riemenschneider, Manuel Mayhaus, Bernd Ibach, Gilles Gasparoni, Sabrina Pichler, Wei Gu, Martin Rossor, Nick Fox, Jason Warren, Maria Spillantini, Huw Morris, Patrizia Rizzu, Peter Heutink, Julie Snowden, Sara Rollinson, Anna Richardson, Alexander Gerhard, Amalia Bruni, Raffaele Maletta, Francesca Frangipane, Chiara Cupidi, Livia Bernardi, Maria Anfossi, Maura Gallo, Maria Conidi, Nicoletta Smirne, Rosa Rademakers, Matt Baker, Dennis Dickson, Neil Graff-Radford, Ronald Petersen, David Knopman, Keith Josephs, Bradley Boeve, Joseph Parisi, William Seeley, Bruce Miller, Anna Karydas, Howard Rosen, John van Swieten, Elise Dopper, Harro Seelaar, Yolande Pijnenburg, Philip Scheltens, Giancarlo Logroscino, Rosa Capozzo, Valeria Novelli, Annibale Puca, Massimo Franceschi, Alfredo Postiglione, Graziella Milan, Paolo Sorrentino, Mark Kristiansen, Huei-Hsin Chiang, Caroline Graff, Florence Pasquier, Adeline Rollin, Vincent Deramecourt, Florence Lebert, Dimitrios Kapogiannis, Luigi Ferrucci, Stuart Pickering-Brown, Andrew Singleton, John Hardy, Parastoo Momeni

    Research output: Contribution to journalArticle

    137 Citations (Scopus)

    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 × 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.

    Original languageEnglish
    Pages (from-to)686-699
    Number of pages14
    JournalLancet Neurology
    Volume13
    Issue number7
    DOIs
    Publication statusPublished - 2014

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  • Cite this

    Ferrari, R., Hernandez, D., Nalls, M., Rohrer, J., Ramasamy, A., Kwok, J., Dobson-Stone, C., Brooks, W., Schofield, P., Halliday, G., Hodges, J., Piguet, O., Bartley, L., Thompson, E., Haan, E., Hernandez, I., Ruiz, A., Boada, M., Borroni, B., ... Momeni, P. (2014). Frontotemporal dementia and its subtypes: a genome-wide association study. Lancet Neurology, 13(7), 686-699. https://doi.org/10.1016/S1474-4422(14)70065-1