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Multicenter Study
. 2014 Jul;13(7):686-99.
doi: 10.1016/S1474-4422(14)70065-1.

Frontotemporal Dementia and Its Subtypes: A Genome-Wide Association Study

Raffaele Ferrari  1 Dena G Hernandez  2 Michael A Nalls  3 Jonathan D Rohrer  4 Adaikalavan Ramasamy  5 John B J Kwok  6 Carol Dobson-Stone  6 William S Brooks  6 Peter R Schofield  6 Glenda M Halliday  6 John R Hodges  6 Olivier Piguet  6 Lauren Bartley  7 Elizabeth Thompson  8 Eric Haan  8 Isabel Hernández  9 Agustín Ruiz  9 Mercè Boada  10 Barbara Borroni  11 Alessandro Padovani  11 Carlos Cruchaga  12 Nigel J Cairns  13 Luisa Benussi  14 Giuliano Binetti  14 Roberta Ghidoni  15 Gianluigi Forloni  16 Daniela Galimberti  17 Chiara Fenoglio  17 Maria Serpente  17 Elio Scarpini  17 Jordi Clarimón  18 Alberto Lleó  18 Rafael Blesa  18 Maria Landqvist Waldö  19 Karin Nilsson  19 Christer Nilsson  20 Ian R A Mackenzie  21 Ging-Yuek R Hsiung  22 David M A Mann  23 Jordan Grafman  24 Christopher M Morris  25 Johannes Attems  26 Timothy D Griffiths  27 Ian G McKeith  28 Alan J Thomas  29 P Pietrini  30 Edward D Huey  31 Eric M Wassermann  32 Atik Baborie  33 Evelyn Jaros  34 Michael C Tierney  32 Pau Pastor  35 Cristina Razquin  36 Sara Ortega-Cubero  37 Elena Alonso  36 Robert Perneczky  38 Janine Diehl-Schmid  39 Panagiotis Alexopoulos  39 Alexander Kurz  39 Innocenzo Rainero  40 Elisa Rubino  40 Lorenzo Pinessi  40 Ekaterina Rogaeva  41 Peter St George-Hyslop  42 Giacomina Rossi  43 Fabrizio Tagliavini  43 Giorgio Giaccone  43 James B Rowe  44 Johannes C M Schlachetzki  45 James Uphill  46 John Collinge  46 Simon Mead  46 Adrian Danek  47 Vivianna M Van Deerlin  48 Murray Grossman  48 John Q Trojanowski  48 Julie van der Zee  49 William Deschamps  49 Tim Van Langenhove  49 Marc Cruts  49 Christine Van Broeckhoven  49 Stefano F Cappa  50 Isabelle Le Ber  51 Didier Hannequin  52 Véronique Golfier  53 Martine Vercelletto  54 Alexis Brice  51 Benedetta Nacmias  55 Sandro Sorbi  55 Silvia Bagnoli  55 Irene Piaceri  55 Jørgen E Nielsen  56 Lena E Hjermind  56 Matthias Riemenschneider  57 Manuel Mayhaus  58 Bernd Ibach  59 Gilles Gasparoni  58 Sabrina Pichler  58 Wei Gu  60 Martin N Rossor  61 Nick C Fox  61 Jason D Warren  61 Maria Grazia Spillantini  62 Huw R Morris  63 Patrizia Rizzu  64 Peter Heutink  64 Julie S Snowden  65 Sara Rollinson  65 Anna Richardson  66 Alexander Gerhard  67 Amalia C Bruni  68 Raffaele Maletta  68 Francesca Frangipane  68 Chiara Cupidi  68 Livia Bernardi  68 Maria Anfossi  68 Maura Gallo  68 Maria Elena Conidi  68 Nicoletta Smirne  68 Rosa Rademakers  69 Matt Baker  69 Dennis W Dickson  69 Neill R Graff-Radford  70 Ronald C Petersen  71 David Knopman  71 Keith A Josephs  71 Bradley F Boeve  71 Joseph E Parisi  72 William W Seeley  73 Bruce L Miller  73 Anna M Karydas  73 Howard Rosen  73 John C van Swieten  74 Elise G P Dopper  75 Harro Seelaar  75 Yolande A L Pijnenburg  76 Philip Scheltens  76 Giancarlo Logroscino  77 Rosa Capozzo  77 Valeria Novelli  78 Annibale A Puca  79 Massimo Franceschi  80 Alfredo Postiglione  81 Graziella Milan  82 Paolo Sorrentino  82 Mark Kristiansen  83 Huei-Hsin Chiang  84 Caroline Graff  84 Florence Pasquier  85 Adeline Rollin  85 Vincent Deramecourt  85 Florence Lebert  85 Dimitrios Kapogiannis  86 Luigi Ferrucci  87 Stuart Pickering-Brown  65 Andrew B Singleton  3 John Hardy  88 Parastoo Momeni  89
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Free PMC article
Multicenter Study

Frontotemporal Dementia and Its Subtypes: A Genome-Wide Association Study

Raffaele Ferrari et al. Lancet Neurol. .
Free PMC article

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.

Conflict of interest statement

Declaration of interests

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, GYRH, DMAM, JG, CMM, JA, TDG, IGM, AJT, PP, EDH, EMW, AB, EJ, MCT, PP, CR, SOC, EA, RP, JDS, PA, AK, IR, ER, LP, ER, PStGH, 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, HHC, CG, FP, AR, VD, FL, DK, LF, SPB, JH, PM, and ABS declare no competing interests.

Figures

Figure 1
Figure 1. Manhattan plots identifying regions with genome–wide significant associations
(A) Manhattan plot for the entire dataset of the discovery phase depicts the associated regionat 6p21.3. Single–nucleotide polymorphisms (SNPs) with smallest p values and their location within or in proximity of the nearest genes are shown. (B) Manhattan plot for the behavioural frontotemporal dementia set in the discovery phase depicts the associated region at 11q14.
Figure 2
Figure 2. Manhattan plots identifying regions with genome–wide significant associations
SNPs with smallest p values and their location within or in proximity of the nearest genes are shown.Manhattan plots for semantic dementia (C), progressive nonfluent aphasia (D), and motor neurone disease (E) frontotemporal dementia sets.

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