IMT Institutional Repository: No conditions. Results ordered -Date Deposited. 2024-03-28T16:23:41ZEPrintshttp://eprints.imtlucca.it/images/logowhite.pnghttp://eprints.imtlucca.it/2015-11-10T11:58:34Z2017-03-27T12:24:58Zhttp://eprints.imtlucca.it/id/eprint/2875This item is in the repository with the URL: http://eprints.imtlucca.it/id/eprint/28752015-11-10T11:58:34ZFrontotemporal dementia and its subtypes: a genome-wide association studySummaryBackground 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.Raffaele FerrariDena G HernandezMichael A NallsJonathan D RohrerAdaikalavan RamasamyJohn B J KwokCarol Dobson-StoneWilliam S BrooksPeter R SchofieldGlenda M HallidayJohn R HodgesOlivier PiguetLauren BartleyElizabeth ThompsonEric HaanIsabel HernándezAgustín RuizMercè BoadaBarbara BorroniAlessandro PadovaniCarlos CruchagaNigel J CairnsLuisa BenussiGiuliano BinettiRoberta GhidoniGianluigi ForloniDaniela GalimbertiChiara FenoglioMaria SerpenteElio ScarpiniJordi ClarimónAlberto LleóRafael BlesaMaria Landqvist WaldöKarin NilssonChrister NilssonIan R A MackenzieGing-Yuek R HsiungDavid M A MannJordan GrafmanChristopher M MorrisJohannes AttemsTimothy D GriffithsIan G McKeithAlan J ThomasPietro Pietrinipietro.pietrini@imtlucca.itEdward D HueyEric M. WassermannAtik BaborieEvelyn JarosMichael C. TierneyPau PastorCristina RazquinSara Ortega-CuberoElena AlonsoRobert PerneczkyJanine Diehl-SchmidPanagiotis AlexopoulosAlexander KurzInnocenzo RaineroElisa RubinoLorenzo PinessiEkaterina RogaevaPeter St George-HyslopGiacomina RossiFabrizio TagliaviniGiorgio GiacconeJames B RoweJohannes C M SchlachetzkiJames UphillJohn CollingeSimon MeadAdrian DanekVivianna M Van DeerlinMurray GrossmanJohn Q TrojanowskiJulie van der ZeeWilliam DeschampsTim Van LangenhoveMarc CrutsChristine Van BroeckhovenStefano F CappaIsabelle Le BerDidier HannequinVéronique GolfierMartine VercellettoAlexis BriceBenedetta NacmiasSandro SorbiSilvia BagnoliIrene PiaceriJørgen E NielsenLena E HjermindMatthias RiemenschneiderManuel MayhausBernd IbachGilles GasparoniSabrina PichlerWei GuMartin N RossorNick C FoxJason D WarrenMaria Grazia SpillantiniHuw R MorrisPatrizia RizzuPeter HeutinkJulie S SnowdenSara RollinsonAnna RichardsonAlexander GerhardAmalia C BruniRaffaele MalettaFrancesca FrangipaneChiara CupidiLivia BernardiMaria AnfossiMaura GalloMaria Elena ConidiNicoletta SmirneRosa RademakersMatt BakerDennis W DicksonNeill R. Graff-RadfordRonald C PetersenDavid KnopmanKeith A JosephsBradley F BoeveJoseph E ParisiWilliam W SeeleyBruce L MillerAnna M KarydasHoward RosenJohn C van SwietenElise G P DopperHarro SeelaarYolande A L PijnenburgPhilip ScheltensGiancarlo LogroscinoRosa CapozzoValeria NovelliAnnibale A PucaMassimo FranceschiAlfredo PostiglioneGraziella MilanPaolo SorrentinoMark KristiansenHuei-Hsin ChiangCaroline GraffFlorence PasquierAdeline RollinVincent DeramecourtFlorence LebertDimitrios KapogiannisLuigi FerrucciStuart Pickering-BrownAndrew B SingletonJohn HardyParastoo Momeni