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
N1 - Publisher Copyright:
© 2015 The Authors.
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 - http://www.scopus.com/inward/record.url?scp=84933180683&partnerID=8YFLogxK
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 -