Scientific publications

Genetic variability in SQSTM1 and risk of early-onset Alzheimer dementia: a European Early-Onset Dementia Consortium study

May 15, 2015 | Magazine: Neurobiology of Aging

Cuyvers E(1), van der Zee J(1), Bettens K(1), Engelborghs S(2), Vandenbulcke M(3), Robberecht C(1), Dillen L(1), Merlin C(1), Geerts N(1), Graff C(4), Thonberg H(4), Chiang HH(5), Pastor P(6), Ortega-Cubero S(7), Pastor MA(8), Diehl-Schmid J(9), Alexopoulos P(9), Benussi L(10), Ghidoni R(10), Binetti G(10), Nacmias B(11), Sorbi S(11), Sanchez-Valle R(12), Lladó A(12), Gelpi E(13), Almeida MR(14), Santana I(14), Clarimon J(15), Lleó A(15), Fortea J(15), de Mendonça A(16), Martins M(16), Borroni B(17), Padovani A(17), Matěj R(18), Rohan Z(19), Ruiz A(20), Frisoni GB(21), Fabrizi GM(22), Vandenberghe R(23), De Deyn PP(24), Van Broeckhoven C(25), Sleegers K(26); BELNEU Consortium and of the EU EOD Consortium.

(1) 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.
(2) 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.
(3) Department of Old Age Psychiatry and Memory Clinic, University of Leuven and University Hospitals Leuven Gasthuisberg, Leuven, Belgium.
(4) 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.
(5) Department of Neurobiology, Care Sciences and Society (NVS), Center for Alzheimer Research, Division of Neurogeriatrics, Karolinska Institutet, Huddinge, Sweden.
(6) 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.
(7) 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.
(8) 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.
(9) Department of Psychiatry and Psychotherapy, Technische Universität München, München, Germany.
(10) Molecular Markers Laboratory-Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Centro San Giovanni di Dio-Fatebenefratelli, Brescia, Italy.
(11) Department of Neurosciences, Psychology, Drug Research and Child Health (NEUROFARBA), University of Florence, Florence, Italy.
(12) Alzheimer's Disease and Other Cognitive Disorders Unit, Neurology Department, Hospital Clínic, Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
(13) Neurological Tissue Bank of the Biobanc, Hospital Clinic, Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
(14) Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.
(15) 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.
(16) Faculty of Medicine and Institute of Molecular Medicine, University of Lisbon, Lisbon, Portugal.
(17) Neurology Unit, University of Brescia, Brescia, Italy.
(18) 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.
(19) 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.
(20) Memory Clinic of Fundaciò ACE, Institut Català de Neurociències Aplicades, Barcelona, Spain.
(21) 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.
(22) Department of Neurological and Movements Sciences, Section of Neurology, University Hospital G.B. Rossi, University of Verona, Verona, Italy.
(23) Laboratory for Cognitive Neurology, Department of Neurology, University of Leuven and University Hospitals Leuven Gasthuisberg, Leuven, Belgium.
(24) 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.
(25) 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.
(26) 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.

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.

CITATION  Neurobiol Aging. 2015 May;36(5):2005.e15-22. doi: 10.1016/j.neurobiolaging.2015.02.014.

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