%J The Lancet Neurology
%R 10.1016/S1474-4422(14)70065-1
%N 7
%A Raffaele Ferrari
%A Dena G Hernandez
%A Michael A Nalls
%A Jonathan D Rohrer
%A Adaikalavan Ramasamy
%A John B J Kwok
%A Carol Dobson-Stone
%A William S Brooks
%A Peter R Schofield
%A Glenda M Halliday
%A John R Hodges
%A Olivier Piguet
%A Lauren Bartley
%A Elizabeth Thompson
%A Eric Haan
%A Isabel Hern?ndez
%A Agust?n Ruiz
%A Merc? Boada
%A Barbara Borroni
%A Alessandro Padovani
%A Carlos Cruchaga
%A Nigel J Cairns
%A Luisa Benussi
%A Giuliano Binetti
%A Roberta Ghidoni
%A Gianluigi Forloni
%A Daniela Galimberti
%A Chiara Fenoglio
%A Maria Serpente
%A Elio Scarpini
%A Jordi Clarim?n
%A Alberto Lle?
%A Rafael Blesa
%A Maria Landqvist Wald?
%A Karin Nilsson
%A Christer Nilsson
%A Ian R A Mackenzie
%A Ging-Yuek R Hsiung
%A David M A Mann
%A Jordan Grafman
%A Christopher M Morris
%A Johannes Attems
%A Timothy D Griffiths
%A Ian G McKeith
%A Alan J Thomas
%A Pietro Pietrini
%A Edward D Huey
%A Eric M. Wassermann
%A Atik Baborie
%A Evelyn Jaros
%A Michael C. Tierney
%A Pau Pastor
%A Cristina Razquin
%A Sara Ortega-Cubero
%A Elena Alonso
%A Robert Perneczky
%A Janine Diehl-Schmid
%A Panagiotis Alexopoulos
%A Alexander Kurz
%A Innocenzo Rainero
%A Elisa Rubino
%A Lorenzo Pinessi
%A Ekaterina Rogaeva
%A Peter St George-Hyslop
%A Giacomina Rossi
%A Fabrizio Tagliavini
%A Giorgio Giaccone
%A James B Rowe
%A Johannes C M Schlachetzki
%A James Uphill
%A John Collinge
%A Simon Mead
%A Adrian Danek
%A Vivianna M Van Deerlin
%A Murray Grossman
%A John Q Trojanowski
%A Julie van der Zee
%A William Deschamps
%A Tim Van Langenhove
%A Marc Cruts
%A Christine Van Broeckhoven
%A Stefano F Cappa
%A Isabelle Le Ber
%A Didier Hannequin
%A V?ronique Golfier
%A Martine Vercelletto
%A Alexis Brice
%A Benedetta Nacmias
%A Sandro Sorbi
%A Silvia Bagnoli
%A Irene Piaceri
%A J?rgen E Nielsen
%A Lena E Hjermind
%A Matthias Riemenschneider
%A Manuel Mayhaus
%A Bernd Ibach
%A Gilles Gasparoni
%A Sabrina Pichler
%A Wei Gu
%A Martin N Rossor
%A Nick C Fox
%A Jason D Warren
%A Maria Grazia Spillantini
%A Huw R Morris
%A Patrizia Rizzu
%A Peter Heutink
%A Julie S Snowden
%A Sara Rollinson
%A Anna Richardson
%A Alexander Gerhard
%A Amalia C Bruni
%A Raffaele Maletta
%A Francesca Frangipane
%A Chiara Cupidi
%A Livia Bernardi
%A Maria Anfossi
%A Maura Gallo
%A Maria Elena Conidi
%A Nicoletta Smirne
%A Rosa Rademakers
%A Matt Baker
%A Dennis W Dickson
%A Neill R. Graff-Radford
%A Ronald C Petersen
%A David Knopman
%A Keith A Josephs
%A Bradley F Boeve
%A Joseph E Parisi
%A William W Seeley
%A Bruce L Miller
%A Anna M Karydas
%A Howard Rosen
%A John C van Swieten
%A Elise G P Dopper
%A Harro Seelaar
%A Yolande A L Pijnenburg
%A Philip Scheltens
%A Giancarlo Logroscino
%A Rosa Capozzo
%A Valeria Novelli
%A Annibale A Puca
%A Massimo Franceschi
%A Alfredo Postiglione
%A Graziella Milan
%A Paolo Sorrentino
%A Mark Kristiansen
%A Huei-Hsin Chiang
%A Caroline Graff
%A Florence Pasquier
%A Adeline Rollin
%A Vincent Deramecourt
%A Florence Lebert
%A Dimitrios Kapogiannis
%A Luigi Ferrucci
%A Stuart Pickering-Brown
%A Andrew B Singleton
%A John Hardy
%A Parastoo Momeni
%D 2014
%L eprints2875
%X SummaryBackground 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.
%I Elsevier
%V 13
%P 686 - 699
%T Frontotemporal dementia and its subtypes: a genome-wide association study