title: Effects of Multiple Genetic Loci on Age at Onset in Frontotemporal Dementia.
abstract: In frontotemporal dementia (FTD), age at disease onset (AAO) is unpredictable in both early and late-onset cases; AAO variability is found even in autosomal dominant FTD. The present study was aimed at identifying genetic modifiers modulating AAO in a large cohort of Italian FTD patients. We conducted an association analysis on 411 FTD patients, belonging to 7 Italian Centers, and for whom AAO was available. Population structure was evaluated by principal component analysis to infer continuous axes of genetic variation, and single linear regression models were applied. A genetic score (GS) was calculated on the basis of suggestive single nucleotide polymorphisms (SNPs) found by association analyses. GS showed genome-wide significant slope decrease by -3.86 (95% CI: -4.64 to -3.07, p < 2×10-16) per standard deviation of the GS for 6 SNPs mapping to genes involved in neuronal development and signaling, axonal myelinization, and glutamatergic/GABA neurotransmission. An increase of the GS was associated with a decrease of the AAO. Our data indicate that there is indeed a genetic component that underpins and modulates up to 14.5% of variability of AAO in Italian FTD. Future studies on genetic modifiers in FTD are warranted.
authors.affiliation: Department of Molecular Neuroscience, Institute of Neurology, UCL, London, UK.
authors.forename: Raffaele
authors.initials: R
authors.lastname: Ferrari
authors.affiliation: Department of Brain and Behavioural Sciences, Medical and Genomic Statistics Unit, University of Pavia, Pavia, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Grassi
authors.affiliation: Department of Brain and Behavioural Sciences, Medical and Genomic Statistics Unit, University of Pavia, Pavia, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Graziano
authors.affiliation: Department of Brain and Behavioural Sciences, Medical and Genomic Statistics Unit, University of Pavia, Pavia, Italy.
authors.forename: Fernando
authors.initials: F
authors.lastname: Palluzzi
authors.affiliation: Department of Laboratories, III Laboratory of Analysis, Brescia Hospital, Brescia, Italy.
authors.forename: Silvana
authors.initials: S
authors.lastname: Archetti
authors.affiliation: Department of Clinical and Experimental Science, Neurology Unit, University of Brescia, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Bonomi
authors.affiliation: Neurogenetic Regional Centre ASPCZ Lamezia Terme, Lamezia Terme, Italy.
authors.forename: Amalia C
authors.initials: AC
authors.lastname: Bruni
authors.affiliation: Neurogenetic Regional Centre ASPCZ Lamezia Terme, Lamezia Terme, Italy.
authors.forename: Raffaele G
authors.initials: RG
authors.lastname: Maletta
authors.affiliation: Neurogenetic Regional Centre ASPCZ Lamezia Terme, Lamezia Terme, Italy.
authors.forename: Livia
authors.initials: L
authors.lastname: Bernardi
authors.affiliation: Neurogenetic Regional Centre ASPCZ Lamezia Terme, Lamezia Terme, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Cupidi
authors.affiliation: Neurogenetic Regional Centre ASPCZ Lamezia Terme, Lamezia Terme, Italy.
authors.forename: Rosanna
authors.initials: R
authors.lastname: Colao
authors.affiliation: Department of Neuroscience, Neurology I, University of Torino and Cittá della Salute e della Scienza di Torino, Turin, Italy.
authors.forename: Innocenzo
authors.initials: I
authors.lastname: Rainero
authors.affiliation: Department of Neuroscience, Neurology I, University of Torino and Cittá della Salute e della Scienza di Torino, Turin, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Rubino
authors.affiliation: Department of Neuroscience, Neurology I, University of Torino and Cittá della Salute e della Scienza di Torino, Turin, Italy.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Pinessi
authors.affiliation: Department of Pathophysiology and Transplantation, Neurology Unit, University of Milan, Fondazione Cà Granda, IRCCS Ospedale Policlinico, Milan, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Galimberti
authors.affiliation: Department of Pathophysiology and Transplantation, Neurology Unit, University of Milan, Fondazione Cà Granda, IRCCS Ospedale Policlinico, Milan, Italy.
authors.forename: Elio
authors.initials: E
authors.lastname: Scarpini
authors.affiliation: Department of Pathophysiology and Transplantation, Neurology Unit, University of Milan, Fondazione Cà Granda, IRCCS Ospedale Policlinico, Milan, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Serpente
authors.affiliation: Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, Florence, Italy.
authors.forename: Benedetta
authors.initials: B
authors.lastname: Nacmias
authors.affiliation: Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, Florence, Italy.
authors.forename: Irene
authors.initials: I
authors.lastname: Piaceri
authors.affiliation: Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, Florence, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Bagnoli
authors.affiliation: Division of Neurology V and Neuropathology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy.
authors.forename: Giacomina
authors.initials: G
authors.lastname: Rossi
authors.affiliation: Division of Neurology V and Neuropathology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Giaccone
authors.affiliation: Division of Neurology V and Neuropathology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Tagliavini
authors.affiliation: Molecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy.
authors.forename: Luisa
authors.initials: L
authors.lastname: Benussi
authors.affiliation: Molecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy.|MAC Memory Center, IRCCS Istituto Centro San Giovanni di Dio-Fatebenefratelli, Brescia, Italy.
authors.forename: Giuliano
authors.initials: G
authors.lastname: Binetti
authors.affiliation: Molecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Ghidoni
authors.affiliation: Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Singleton
authors.affiliation: Department of Molecular Neuroscience, Institute of Neurology, UCL, London, UK.
authors.forename: John
authors.initials: J
authors.lastname: Hardy
authors.affiliation: Department of Internal Medicine, Laboratory of Neurogenetics, Texas Tech University Health Science Center, Lubbock, TX, USA.
authors.forename: Parastoo
authors.initials: P
authors.lastname: Momeni
authors.affiliation: Department of Clinical and Experimental Science, Neurology Unit, University of Brescia, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Padovani
authors.affiliation: Department of Clinical and Experimental Science, Neurology Unit, University of Brescia, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Borroni
mesh_terms: D000328:Adult; D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D015331:Cohort Studies; D057180:Frontotemporal Dementia / Q000453:epidemiology / Q000235:genetics*; D056726:Genetic Association Studies; D056426:Genetic Loci; D006801:Humans; D007558:Italy; D016014:Linear Models; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D025341:Principal Component Analysis
keywords: Age at onset; GWAS; frontotemporal dementia; polymorphism