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

被引：31

作者：

Cuyvers, Elise ^{[1
,2
,3
]}

van der Zee, Julie ^{[1
,2
,3
]}

Bettens, Karolien ^{[1
,2
,3
]}

Engelborghs, Sebastiaan ^{[2
,3
,4
,5
]}

Vandenbulcke, Mathieu ^{[6
,7
,8
]}

Robberecht, Caroline ^{[1
,2
,3
]}

Dillen, Lubina ^{[1
,2
,3
]}

Merlin, Celine ^{[1
,2
,3
]}

Geerts, Nathalie ^{[1
,2
,3
]}

Graff, Caroline ^{[9
,10
]}

Thonberg, Hakan ^{[9
,10
]}

Chiang, Huei-Hsin ^{[9
]}

Pastor, Pau ^{[11
,12
,13
]}

Ortega-Cubero, Sara ^{[11
,13
]}

Pastor, Maria A. ^{[13
,14
,15
]}

Diehl-Schmid, Janine ^{[16
]}

Alexopoulos, Panagiotis ^{[16
]}

Benussi, Luisa ^{[17
]}

Ghidoni, Roberta ^{[17
]}

Binetti, Giuliano ^{[17
]}

Nacmias, Benedetta ^{[18
]}

Sorbi, Sandro ^{[18
]}

Sanchez-Valle, Raquel ^{[19
]}

Llado, Albert ^{[19
]}

Gelpi, Ellen ^{[20
]}

Almeida, Maria Rosario ^{[21
]}

Santana, Isabel ^{[21
]}

Clarimon, Jordi ^{[13
,22
]}

Lleo, Alberto ^{[13
,22
]}

Fortea, Juan ^{[13
,22
]}

de Mendonca, Alexandre ^{[23
,24
]}

Martins, Madalena ^{[23
,24
]}

Borroni, Barbara ^{[25
]}

Padovani, Alessandro ^{[25
]}

Matej, Radoslav ^{[26
,27
]}

Rohan, Zdenek ^{[26
,27
,28
]}

Ruiz, Agustin ^{[29
]}

Frisoni, Giovanni B. ^{[30
,31
,32
,33
]}

Fabrizi, Gian Maria ^{[34
]}

Vandenberghe, Rik ^{[8
,35
]}

De Deyn, Peter P. ^{[2
,3
,4
,5
,36
,37
]}

Van Broeckhoven, Christine ^{[1
,2
,3
]}

Sleegers, Kristel ^{[1
,2
,3
]}

机构：

[1] VIB, Dept Mol Genet, Antwerp, Belgium

[2] Univ Antwerp, Inst Born Bunge, Neurogenet Lab, B-2020 Antwerp, Belgium

[3] Univ Antwerp, Inst Born Bunge, Lab Neurochem & Behav, B-2020 Antwerp, Belgium

[4] Hosp Network Antwerp Middelheim & Hoge Beuken, Dept Neurol, Antwerp, Belgium

[5] Hosp Network Antwerp Middelheim & Hoge Beuken, Memory Clin, Antwerp, Belgium

[6] Univ Leuven, Dept Old Age Psychiat, Leuven, Belgium

[7] Univ Leuven, Memory Clin, Leuven, Belgium

[8] Univ Hosp Leuven Gasthuisberg, Leuven, Belgium

[9] Karolinska Inst, Div Neurogeriatr, Ctr Alzheimer Res, Dept Neurobiol Care Sci & Soc NVS, Huddinge, Sweden

[10] Karolinska Univ Hosp, Genet Unit, Dept Geriatr Med, Stockholm, Sweden

[11] Univ Navarra, Ctr Appl Med Res, Div Neurosci, Neurogenet Lab, E-31080 Pamplona, Spain

[12] Hosp Univ Mutua Terrassa, Dept Neurol, Barcelona, Spain

[13] Inst Salud Carlos III, Ctr Invest Biomed Red Enfermedades Neurodegenerat, Madrid, Spain

[14] Univ Navarra, Ctr Appl Med Res CIMA, Div Neurosci, Neuroimaging Lab, E-31080 Pamplona, Spain

[15] Univ Navarra, Sch Med, Univ Navarra Clin, Dept Neurol, E-31080 Pamplona, Spain

[16] Tech Univ Munich, Dept Psychiat & Psychotherapy, D-80290 Munich, Germany

[17] Ist Ctr San Giovanni Dio Fatebenefratelli, IRCCS, Mol Markers Lab, Brescia, Italy

[18] Univ Florence, Dept Neurosci Psychol Drug Res & Child Hlth NEURO, Florence, Italy

[19] Hosp Clin Barcelona, Dept Neurol, Alzheimers Dis & Other Cognit Disorders Unit, Inst Invest Biomed August Pi & Sunyer IDIBAPS, Barcelona, Spain

[20] Hosp Clin Barcelona, Inst Invest Biomed August Pi & Sunyer IDIBAPS, Neurol Tissue Bank Biobanc, Barcelona, Spain

[21] Univ Coimbra, Ctr Neurosci & Cell Biol, Coimbra, Portugal

[22] Univ Autonoma Barcelona, Dept Neurol, IIB St Pau, Hosp Santa Creu & St Pau, E-08193 Barcelona, Spain

[23] Univ Lisbon, Fac Med, P-1699 Lisbon, Portugal

[24] Univ Lisbon, Inst Mol Med, P-1699 Lisbon, Portugal

[25] Univ Brescia, Neurol Unit, Brescia, Italy

[26] Charles Univ Prague, Fac Med 1, Dept Neurol, Ctr Clin Neurosci, Prague, Czech Republic

[27] Thomayer Hosp, Dept Pathol & Mol Med, Prague, Czech Republic

[28] Charles Univ Prague, Med Fac 3, Inst Pathol, Prague, Czech Republic

[29] Inst Catala Neurociencies Aplicades, Memory Clin Fundacio ACE, Barcelona, Spain

[30] Hop Cantonal Univ Geneva, Dept Med Interne Rehabil & Geriatrie, Geneva, Switzerland

[31] Hop Cantonal Univ Geneva, Dept Sante Mentale & Psychiat, Geneva, Switzerland

[32] Univ Geneva, Geneva, Switzerland

[33] IRCCS Fatebenefratelli, Alzheimers Neuroimaging & Epidemiol Lab, Brescia, Italy

[34] Univ Verona, Univ Hosp GB Rossi, Neurol Sect, Dept Neurol & Movements Sci, I-37100 Verona, Italy

[35] Univ Leuven, Dept Neurol, Lab Cognit Neurol, Leuven, Belgium

[36] Univ Groningen, Univ Med Ctr Groningen, Dept Neurol, Groningen, Netherlands

[37] Univ Groningen, Univ Med Ctr Groningen, Alzheimer Res Ctr, Groningen, Netherlands

来源：

NEUROBIOLOGY OF AGING | 2015年 / 36卷 / 05期

基金：

瑞典研究理事会;

关键词：

SQSTM1/p62; Alzheimer's disease; Rare variants; Meta-analysis; European early-onset dementia consortium; PAGETS-DISEASE; FRONTOTEMPORAL DEMENTIA; NATIONAL INSTITUTE; SEQUESTOSOME; 1/P62; MUTATIONS; BONE; P62; SUSCEPTIBILITY; PATHOGENESIS; INCLUSIONS;

D O I：

10.1016/j.neurobiolaging.2015.02.014

中图分类号：

R592 [老年病学]; C [社会科学总论];

学科分类号：

03 ; 0303 ; 100203 ;

摘要：

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 earlyonset 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. (C) 2015 The Authors. Published by Elsevier Inc.

引用

页码：2005.e15 / 2005.e22

页数：8

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