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