title: A genome-wide screening and SNPs-to-genes approach to identify novel genetic risk factors associated with frontotemporal dementia.
abstract: Frontotemporal dementia (FTD) is the second most prevalent form of early onset dementia after Alzheimer's disease (AD). We performed a case-control association study in an Italian FTD cohort (n = 530) followed by the novel single nucleotide polymorphisms (SNPs)-to-genes approach and functional annotation analysis. We identified 2 novel potential loci for FTD. Suggestive SNPs reached p-values ∼10(-7) and odds ratio > 2.5 (2p16.3) and 1.5 (17q25.3). Suggestive alleles at 17q25.3 identified a disease-associated haplotype causing decreased expression of -cis genes such as RFNG and AATK involved in neuronal genesis and differentiation and axon outgrowth, respectively. We replicated this locus through the SNPs-to-genes approach. Our functional annotation analysis indicated significant enrichment for functions of the brain (neuronal genesis, differentiation, and maturation), the synapse (neurotransmission and synapse plasticity), and elements of the immune system, the latter supporting our recent international FTD-genome-wide association study. This is the largest genome-wide study in Italian FTD to date. Although our results are not conclusive, we set the basis for future replication studies and identification of susceptible molecular mechanisms involved in FTD pathogenesis.
authors.affiliation: Department of Molecular Neuroscience, Institute of Neurology, UCL, London, UK; Laboratory of Neurogenetics, Department of Internal Medicine, Texas Tech University Health Science Center, Lubbock, TX, USA. Electronic address: r.ferrari@ucl.ac.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 Health Sciences, University of Milan at San Paolo Hospital, Milan, Italy.
authors.forename: Erika
authors.initials: E
authors.lastname: Salvi
authors.affiliation: Neurology Clinic, University of Brescia, Brescia, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Borroni
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 Brain and Behavioural Sciences, Medical and Genomic Statistics Unit, University of Pavia, Pavia, Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: Pepe
authors.affiliation: Department of Health Sciences, University of Milan at San Paolo Hospital, Milan, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: D'Avila
authors.affiliation: Neurology Clinic, University of Brescia, Brescia, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Padovani
authors.affiliation: Neurology Clinic, University of Brescia, Brescia, Italy.
authors.forename: Silvana
authors.initials: S
authors.lastname: Archetti
authors.affiliation: Neurology I, Department of Neuroscience, University of Torino and Città della Salute e della Scienza di Torino, Turin, Italy.
authors.forename: Innocenzo
authors.initials: I
authors.lastname: Rainero
authors.affiliation: Neurology I, Department of Neuroscience, University of Torino and Città della Salute e della Scienza di Torino, Turin, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Rubino
authors.affiliation: Neurology I, Department of Neuroscience, University of Torino and Città della Salute e della Scienza di Torino, Turin, Italy.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Pinessi
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.
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: Neurology Unit, Department of Pathophysiology and Transplantation, University of Milan, Fondazione Cà Granda, IRCCS Ospedale Policlinico, Milan, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Galimberti
authors.affiliation: Neurology Unit, Department of Pathophysiology and Transplantation, University of Milan, Fondazione Cà Granda, IRCCS Ospedale Policlinico, Milan, Italy.
authors.forename: Elio
authors.initials: E
authors.lastname: Scarpini
authors.affiliation: Neurology Unit, Department of Pathophysiology and Transplantation, University of Milan, Fondazione Cà Granda, IRCCS Ospedale Policlinico, Milan, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Serpente
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: 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: 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: Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Postiglione
authors.affiliation: Geriatric Center Frullone-ASL Napoli 1 Centro, Naples, Italy.
authors.forename: Graziella
authors.initials: G
authors.lastname: Milan
authors.affiliation: Department of Neurology, IRCCS Multimedica, Milan, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Franceschi
authors.affiliation: Department of Medicine and Surgery, University of Salerno, Baronissi, Salerno, Italy; Cardiovascular Research Unit, IRCCS Multimedica, Milan, Italy.
authors.forename: Annibale A
authors.initials: AA
authors.lastname: Puca
authors.affiliation: Department of Molecular Cardiology, IRCCS Fondazione S. Maugeri, Pavia, Italy.
authors.forename: Valeria
authors.initials: V
authors.lastname: Novelli
authors.affiliation: Department of Health Sciences, University of Milan at San Paolo Hospital, Milan, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Barlassina
authors.affiliation: Hypertension and Related Disease Centre, AOU-University of Sassari, Sassari, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: Glorioso
authors.affiliation: Chair of Nephrology, Nephrology and Dialysis and Hypertension Unit, San Raffaele Scientific Institute, Università Vita Salute San Raffaele, Milano, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Manunta
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 Health Sciences, University of Milan at San Paolo Hospital, Milan, Italy; Institute of Biomedical Technologies, Italian National Research Council, Milan, Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: Cusi
authors.affiliation: Department of Molecular Neuroscience, Institute of Neurology, UCL, London, UK.
authors.forename: John
authors.initials: J
authors.lastname: Hardy
authors.affiliation: Laboratory of Neurogenetics, Department of Internal Medicine, Texas Tech University Health Science Center, Lubbock, TX, USA.
authors.forename: Parastoo
authors.initials: P
authors.lastname: Momeni
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D051017:Apoptosis Regulatory Proteins / Q000235:genetics; D001369:Axons / Q000502:physiology; D001921:Brain / Q000502:physiology*; D016022:Case-Control Studies; D002454:Cell Differentiation / Q000235:genetics; D015331:Cohort Studies; D005260:Female; D057180:Frontotemporal Dementia / Q000235:genetics*; D055106:Genome-Wide Association Study / Q000379:methods*; D005964:Glucosyltransferases / Q000235:genetics; D006239:Haplotypes; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics; D008297:Male; D008875:Middle Aged; D055495:Neurogenesis / Q000235:genetics; D009474:Neurons / Q000166:cytology; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011505:Protein-Tyrosine Kinases / Q000235:genetics; D012307:Risk Factors
chemical_list: D051017:Apoptosis Regulatory Proteins; D036341:Intercellular Signaling Peptides and Proteins; D005964:Glucosyltransferases; C491318:RFNG protein, human; C118137:AATK protein, human; D011505:Protein-Tyrosine Kinases
keywords: Association study; Case-control; Frontotemporal dementia; Functional annotation; Genetic risk factors; Population