Genetic variability in SQSTM1 and risk of early-onset Alzheimer dementia: A European early-onset dementia consortium study

on behalf of the BELNEU Consortium and of the EU EOD Consortium

doi:10.1016/j.neurobiolaging.2015.02.014

Genetic variability in SQSTM1 and risk of early-onset Alzheimer dementia: A European early-onset dementia consortium study

on behalf of the BELNEU Consortium and of the EU EOD Consortium

Department of Molecular Genetics
VIB Center for Inflammation Research
Antwerp University
Hospital Network Antwerp Middelheim and Hoge Beuken
Leuven University Center for Metabolic Bone Diseases
Karolinska Institutet
Karolinska Institutet at Karolinska University Hospital
Center for Applied Medical Research
Hospital Mútua de Terrassa
National Institute of Health Carlos III
Clínica Universitaria de Navarra
Technical University of Munich
IRCCS Istituto Centro San Giovanni di Dio-Fatebenefratelli
University of Florence
Hospital Clínic, CIBERNED, IDIBAPS
University of Coimbra, Center for Neuroscience and Cell Biology
Universitat Autònoma de Barcelona
Faculdade de Medicina, Universidade de Lisboa
University of Brescia
Charles University
Thomayer Hospital
Institut Català de Neurociències Aplicades
Geneva University Hospitals
University of Verona
University Medical Center Groningen

Research output: Contribution to journal › Article › peer-review

33 Scopus citations

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 ratio_p.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.

Original language	English
Pages (from-to)	2005.e15-2005.e22
Journal	Neurobiology of Aging
Volume	36
Issue number	5
DOIs	https://doi.org/10.1016/j.neurobiolaging.2015.02.014
State	Published - 2015
Externally published	Yes

Keywords

Alzheimer's disease
European early-onset dementia consortium
Meta-analysis
Rare variants
SQSTM1/p62

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10.1016/j.neurobiolaging.2015.02.014

Cite this

@article{e2116e6407444b2e80f31b0da0a0bd4f,

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.",

keywords = "Alzheimer's disease, European early-onset dementia consortium, Meta-analysis, Rare variants, SQSTM1/p62",

author = "\{on behalf of the BELNEU Consortium and of the EU EOD Consortium\} and Elise Cuyvers and \{van der Zee\}, Julie and Karolien Bettens and Sebastiaan Engelborghs and Mathieu Vandenbulcke and Caroline Robberecht and Lubina Dillen and C{\'e}line Merlin and Nathalie Geerts and Caroline Graff and H{\aa}kan Thonberg and Chiang, \{Huei Hsin\} and Pau Pastor and Sara Ortega-Cubero and Pastor, \{Maria A.\} and Janine Diehl-Schmid and Panagiotis Alexopoulos and Luisa Benussi and Roberta Ghidoni and Giuliano Binetti and Benedetta Nacmias and Sandro Sorbi and Raquel Sanchez-Valle and Albert Llad{\'o} and Ellen Gelpi and Almeida, \{Maria Ros{\'a}rio\} and Isabel Santana and Jordi Clarimon and Alberto Lle{\'o} and Juan Fortea and \{de Mendon{\c c}a\}, Alexandre and Madalena Martins and Barbara Borroni and Alessandro Padovani and Radoslav Mat{\v e}j and Zdenek Rohan and Agust{\'i}n Ruiz and Frisoni, \{Giovanni B.\} and Fabrizi, \{Gian Maria\} and Rik Vandenberghe and \{De Deyn\}, \{Peter P.\} and \{Van Broeckhoven\}, Christine and Kristel Sleegers",

note = "Publisher Copyright: {\textcopyright} 2015 The Authors.",

year = "2015",

doi = "10.1016/j.neurobiolaging.2015.02.014",

language = "English",

volume = "36",

pages = "2005.e15--2005.e22",

journal = "Neurobiology of Aging",

issn = "0197-4580",

publisher = "Elsevier Inc.",

number = "5",

}

TY - JOUR

T1 - Genetic variability in SQSTM1 and risk of early-onset Alzheimer dementia

T2 - A European early-onset dementia consortium study

AU - on behalf of the BELNEU Consortium and of the EU EOD Consortium

AU - Cuyvers, Elise

AU - van der Zee, Julie

AU - Bettens, Karolien

AU - Engelborghs, Sebastiaan

AU - Vandenbulcke, Mathieu

AU - Robberecht, Caroline

AU - Dillen, Lubina

AU - Merlin, Céline

AU - Geerts, Nathalie

AU - Graff, Caroline

AU - Thonberg, Håkan

AU - Chiang, Huei Hsin

AU - Pastor, Pau

AU - Ortega-Cubero, Sara

AU - Pastor, Maria A.

AU - Diehl-Schmid, Janine

AU - Alexopoulos, Panagiotis

AU - Benussi, Luisa

AU - Ghidoni, Roberta

AU - Binetti, Giuliano

AU - Nacmias, Benedetta

AU - Sorbi, Sandro

AU - Sanchez-Valle, Raquel

AU - Lladó, Albert

AU - Gelpi, Ellen

AU - Almeida, Maria Rosário

AU - Santana, Isabel

AU - Clarimon, Jordi

AU - Lleó, Alberto

AU - Fortea, Juan

AU - de Mendonça, Alexandre

AU - Martins, Madalena

AU - Borroni, Barbara

AU - Padovani, Alessandro

AU - Matěj, Radoslav

AU - Rohan, Zdenek

AU - Ruiz, Agustín

AU - Frisoni, Giovanni B.

AU - Fabrizi, Gian Maria

AU - Vandenberghe, Rik

AU - De Deyn, Peter P.

AU - Van Broeckhoven, Christine

AU - Sleegers, Kristel

PY - 2015

Y1 - 2015

N2 - 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.

AB - 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.

KW - Alzheimer's disease

KW - European early-onset dementia consortium

KW - Meta-analysis

KW - Rare variants

KW - SQSTM1/p62

UR - https://www.scopus.com/pages/publications/84933180683

U2 - 10.1016/j.neurobiolaging.2015.02.014

DO - 10.1016/j.neurobiolaging.2015.02.014

M3 - Article

C2 - 25796131

AN - SCOPUS:84933180683

SN - 0197-4580

VL - 36

SP - 2005.e15-2005.e22

JO - Neurobiology of Aging

JF - Neurobiology of Aging

IS - 5

ER -

Genetic variability in SQSTM1 and risk of early-onset Alzheimer dementia: A European early-onset dementia consortium study

Abstract

Keywords

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