title: Genetic variability in SQSTM1 and risk of early-onset Alzheimer dementia: a European early-onset dementia consortium study.
abstract: Meta-analysis of existing genome-wide association studies on Alzheimer's disease (AD) showed subgenome-wide association of an intronic variant in the sequestosome 1 (SQSTM1) gene with AD. We performed targeted resequencing of SQSTM1 in Flanders-Belgian AD patients selected to be enriched for a genetic background (n = 435) and geographically matched nonaffected individuals (n = 872) to investigate the role of both common and rare SQSTM1 variants. Results were extended to the European early-onset dementia cohorts (926 early-onset Alzheimer's disease [EOAD] patients and 1476 nonaffected individuals). Of the 61 detected exonic variants in SQSTM1, the majority were rare (n = 57). Rare variant (minor allele frequency <0.01) burden analysis did not reveal an increased frequency of rare variants in EOAD patients in any of the separate study populations nor when meta-analyzing all cohorts. Common variants p.D292= and p.R312= showed nominal association with AD (odds ratiop.D292= = 1.11 [95% confidence interval = 1-1.22], p = 0.04), only when including the Flanders-Belgian cohort in the meta-analysis. We cannot exclude a role of SQSTM1 genetic variability in late-onset AD, but our data indicate that SQSTM1 does not play a major role in the etiology of EOAD.
authors: Department of Molecular Genetics, VIB, Antwerp, Belgium; Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium; Laboratory of Neurochemistry and Behavior, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
authors: Elise
authors: E
authors: Cuyvers
authors: Department of Molecular Genetics, VIB, Antwerp, Belgium; Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium; Laboratory of Neurochemistry and Behavior, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
authors: Julie
authors: J
authors: van der Zee
authors: Department of Molecular Genetics, VIB, Antwerp, Belgium; Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium; Laboratory of Neurochemistry and Behavior, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
authors: Karolien
authors: K
authors: Bettens
authors: Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium; Laboratory of Neurochemistry and Behavior, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium; Department of Neurology and Memory Clinic, Hospital Network Antwerp Middelheim and Hoge Beuken, Antwerp, Belgium.
authors: Sebastiaan
authors: S
authors: Engelborghs
authors: Department of Old Age Psychiatry and Memory Clinic, University of Leuven and University Hospitals Leuven Gasthuisberg, Leuven, Belgium.
authors: Mathieu
authors: M
authors: Vandenbulcke
authors: Department of Molecular Genetics, VIB, Antwerp, Belgium; Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium; Laboratory of Neurochemistry and Behavior, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
authors: Caroline
authors: C
authors: Robberecht
authors: Department of Molecular Genetics, VIB, Antwerp, Belgium; Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium; Laboratory of Neurochemistry and Behavior, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
authors: Lubina
authors: L
authors: Dillen
authors: Department of Molecular Genetics, VIB, Antwerp, Belgium; Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium; Laboratory of Neurochemistry and Behavior, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
authors: Céline
authors: C
authors: Merlin
authors: Department of Molecular Genetics, VIB, Antwerp, Belgium; Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium; Laboratory of Neurochemistry and Behavior, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
authors: Nathalie
authors: N
authors: Geerts
authors: Department of Neurobiology, Care Sciences and Society (NVS), Center for Alzheimer Research, Division of Neurogeriatrics, Karolinska Institutet, Huddinge, Sweden; Department of Geriatric Medicine, Genetics Unit, Karolinska University Hospital, Stockholm, Sweden.
authors: Caroline
authors: C
authors: Graff
authors: Department of Neurobiology, Care Sciences and Society (NVS), Center for Alzheimer Research, Division of Neurogeriatrics, Karolinska Institutet, Huddinge, Sweden; Department of Geriatric Medicine, Genetics Unit, Karolinska University Hospital, Stockholm, Sweden.
authors: Håkan
authors: H
authors: Thonberg
authors: Department of Neurobiology, Care Sciences and Society (NVS), Center for Alzheimer Research, Division of Neurogeriatrics, Karolinska Institutet, Huddinge, Sweden.
authors: Huei-Hsin
authors: HH
authors: Chiang
authors: Neurogenetics Laboratory, Division of Neurosciences, Center for Applied Medical Research, Universidad de Navarra, Pamplona, Spain; Department of Neurology, Hospital Universitari Mutua de Terrassa, Terrassa, Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain.
authors: Pau
authors: P
authors: Pastor
authors: Neurogenetics Laboratory, Division of Neurosciences, Center for Applied Medical Research, Universidad de Navarra, Pamplona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain.
authors: Sara
authors: S
authors: Ortega-Cubero
authors: Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain; Neuroimaging Laboratory, Division of Neurosciences, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain; Department of Neurology, Clínica Universidad de Navarra, University of Navarra School of Medicine, Pamplona, Spain.
authors: Maria A
authors: MA
authors: Pastor
authors: Department of Psychiatry and Psychotherapy, Technische Universität München, München, Germany.
authors: Janine
authors: J
authors: Diehl-Schmid
authors: Department of Psychiatry and Psychotherapy, Technische Universität München, München, Germany.
authors: Panagiotis
authors: P
authors: Alexopoulos
authors: Molecular Markers Laboratory-Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Centro San Giovanni di Dio-Fatebenefratelli, Brescia, Italy.
authors: Luisa
authors: L
authors: Benussi
authors: Molecular Markers Laboratory-Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Centro San Giovanni di Dio-Fatebenefratelli, Brescia, Italy.
authors: Roberta
authors: R
authors: Ghidoni
authors: Molecular Markers Laboratory-Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Centro San Giovanni di Dio-Fatebenefratelli, Brescia, Italy.
authors: Giuliano
authors: G
authors: Binetti
authors: Department of Neurosciences, Psychology, Drug Research and Child Health (NEUROFARBA), University of Florence, Florence, Italy.
authors: Benedetta
authors: B
authors: Nacmias
authors: Department of Neurosciences, Psychology, Drug Research and Child Health (NEUROFARBA), University of Florence, Florence, Italy.
authors: Sandro
authors: S
authors: Sorbi
authors: Alzheimer's Disease and Other Cognitive Disorders Unit, Neurology Department, Hospital Clínic, Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors: Raquel
authors: R
authors: Sanchez-Valle
authors: Alzheimer's Disease and Other Cognitive Disorders Unit, Neurology Department, Hospital Clínic, Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors: Albert
authors: A
authors: Lladó
authors: Neurological Tissue Bank of the Biobanc, Hospital Clinic, Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors: Ellen
authors: E
authors: Gelpi
authors: Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.
authors: Maria Rosário
authors: MR
authors: Almeida
authors: Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.
authors: Isabel
authors: I
authors: Santana
authors: Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain; Department of Neurology, IIB Sant Pau, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors: Jordi
authors: J
authors: Clarimon
authors: Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain; Department of Neurology, IIB Sant Pau, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors: Alberto
authors: A
authors: Lleó
authors: Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain; Department of Neurology, IIB Sant Pau, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors: Juan
authors: J
authors: Fortea
authors: Faculty of Medicine and Institute of Molecular Medicine, University of Lisbon, Lisbon, Portugal.
authors: Alexandre
authors: A
authors: de Mendonça
authors: Faculty of Medicine and Institute of Molecular Medicine, University of Lisbon, Lisbon, Portugal.
authors: Madalena
authors: M
authors: Martins
authors: Neurology Unit, University of Brescia, Brescia, Italy.
authors: Barbara
authors: B
authors: Borroni
authors: Neurology Unit, University of Brescia, Brescia, Italy.
authors: Alessandro
authors: A
authors: Padovani
authors: Center of Clinical Neurosciences, Department of Neurology, First Medical Faculty, Charles University in Prague, Czech Republic; Department of Pathology and Molecular Medicine, Thomayer Hospital, Prague, Czech Republic.
authors: Radoslav
authors: R
authors: Matěj
authors: Center of Clinical Neurosciences, Department of Neurology, First Medical Faculty, Charles University in Prague, Czech Republic; Department of Pathology and Molecular Medicine, Thomayer Hospital, Prague, Czech Republic; Institute of Pathology, Third Medical Faculty of Charles University in Prague, Prague, Czech Republic.
authors: Zdenek
authors: Z
authors: Rohan
authors: Memory Clinic of Fundaciò ACE, Institut Català de Neurociències Aplicades, Barcelona, Spain.
authors: Agustín
authors: A
authors: Ruiz
authors: Départements de Médicine Interne Réhabilitation & Gériatrie et de Sante Mentale & Psychiatrie, Hôpitaux Universitaires de Genève et Université de Genève, Geneva, Switzerland; Alzheimer's Neuroimaging and Epidemiology Laboratory, IRCCS Fatebenefratelli, Brescia, Italy.
authors: Giovanni B
authors: GB
authors: Frisoni
authors: Department of Neurological and Movements Sciences, Section of Neurology, University Hospital G.B. Rossi, University of Verona, Verona, Italy.
authors: Gian Maria
authors: GM
authors: Fabrizi
authors: Laboratory for Cognitive Neurology, Department of Neurology, University of Leuven and University Hospitals Leuven Gasthuisberg, Leuven, Belgium.
authors: Rik
authors: R
authors: Vandenberghe
authors: Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium; Laboratory of Neurochemistry and Behavior, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium; Department of Neurology and Memory Clinic, Hospital Network Antwerp Middelheim and Hoge Beuken, Antwerp, Belgium; Department of Neurology and Alzheimer Research Center, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands.
authors: Peter P
authors: PP
authors: De Deyn
authors: Department of Molecular Genetics, VIB, Antwerp, Belgium; Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium; Laboratory of Neurochemistry and Behavior, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium. Electronic address: christine.vanbroeckhoven@molgen.vib-ua.be.
authors: Christine
authors: C
authors: Van Broeckhoven
authors: Department of Molecular Genetics, VIB, Antwerp, Belgium; Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium; Laboratory of Neurochemistry and Behavior, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium. Electronic address: kristel.sleegers@molgen.vib-ua.be.
authors: Kristel
authors: K
authors: Sleegers
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000368:Aged; D000544:Alzheimer Disease / Q000453:epidemiology / Q000235:genetics*; D001530:Belgium / Q000453:epidemiology; D015331:Cohort Studies; D005260:Female; D014644:Genetic Variation / Q000235:genetics*; D006801:Humans; D008297:Male; D015201:Meta-Analysis as Topic; D008875:Middle Aged; D012306:Risk; D017422:Sequence Analysis, DNA; D000071456:Sequestosome-1 Protein
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein
keywords: Alzheimer's disease; European early-onset dementia consortium; Meta-analysis; Rare variants; SQSTM1/p62