Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer's disease

被引：1498

作者：

Hollingworth, Paul ^{[1
]}

Harold, Denise ^{[1
]}

Sims, Rebecca ^{[1
]}

Gerrish, Amy ^{[1
]}

Lambert, Jean-Charles ^{[2
,3
,4
]}

Carrasquillo, Minerva M. ^{[5
]}

Abraham, Richard ^{[1
]}

Hamshere, Marian L. ^{[1
]}

Pahwa, Jaspreet Singh ^{[1
]}

Moskvina, Valentina ^{[1
]}

Dowzell, Kimberley ^{[1
]}

Jones, Nicola ^{[1
]}

Stretton, Alexandra ^{[1
]}

Thomas, Charlene ^{[1
]}

Richards, Alex ^{[1
]}

Ivanov, Dobril ^{[1
]}

Widdowson, Caroline ^{[1
]}

Chapman, Jade ^{[1
]}

Lovestone, Simon ^{[6
,7
]}

Powell, John ^{[7
]}

Proitsi, Petroula ^{[7
]}

Lupton, Michelle K. ^{[7
]}

Brayne, Carol ^{[8
]}

Rubinsztein, David C. ^{[9
]}

Gill, Michael ^{[10
,11
]}

Lawlor, Brian ^{[10
,11
]}

Lynch, Aoibhinn ^{[10
,11
]}

Brown, Kristelle S. ^{[12
]}

Passmore, Peter A. ^{[13
]}

Craig, David ^{[13
]}

McGuinness, Bernadette ^{[13
]}

Todd, Stephen ^{[13
]}

Holmes, Clive ^{[14
]}

Mann, David ^{[15
]}

Smith, A. David ^{[16
]}

Beaumont, Helen ^{[16
]}

Warden, Donald ^{[16
]}

Wilcock, Gordon ^{[17
]}

Love, Seth ^{[18
]}

Kehoe, Patrick G. ^{[18
]}

Hooper, Nigel M. ^{[19
]}

Vardy, Emma R. L. C. ^{[15
,19
,20
]}

Hardy, John ^{[21
,22
]}

Mead, Simon ^{[23
]}

Fox, Nick C. ^{[23
]}

Rossor, Martin ^{[23
]}

Collinge, John ^{[23
]}

Maier, Wolfgang ^{[24
,25
]}

Jessen, Frank ^{[24
]}

Ruether, Eckart ^{[25
,26
,27
]}

机构：

[1] Cardiff Univ, MRC, Ctr Neuropsychiat Genet,Dept Psychol Med & Neurol, Neurosci & Mental Hlth Res Inst,Sch Med, Cardiff, S Glam, Wales

[2] INSERM, U744, F-59019 Lille, France

[3] Inst Pasteur, F-59019 Lille, France

[4] Univ Lille Nord France, F-59000 Lille, France

[5] Mayo Clin, Coll Med, Dept Neurosci, Jacksonville, FL 32224 USA

[6] Kings Coll London, Natl Inst Hlth Res, Biomed Res Ctr Mental Hlth, S London & Maudsley Natl Hlth Serv Fdn Trust, London WC2R 2LS, England

[7] Kings Coll London, Inst Psychiat, Dept Neurosci, London WC2R 2LS, England

[8] Univ Cambridge, Inst Publ Hlth, Cambridge, England

[9] Univ Cambridge, Cambridge Inst Med Res, Cambridge, England

[10] St James Hosp, Mercers Inst Res Aging, Dublin 8, Ireland

[11] Trinity Coll Dublin, Dublin, Ireland

[12] Univ Nottingham, Inst Genet, Queens Med Ctr, Nottingham NG7 2RD, England

[13] Queens Univ Belfast, Ageing Grp, Ctr Publ Hlth, Sch Med Dent & Biomed Sci, Belfast, Antrim, North Ireland

[14] Univ Southampton, Div Clin Neurosci, Sch Med, Southampton, Hants, England

[15] Univ Manchester, Hope Hosp, Neurodegenerat & Mental Hlth Res Grp, Sch Community Based Med, Manchester, Lancs, England

[16] Univ Oxford, John Radcliffe Hosp, Oxford Project Investigate Memory & Ageing OPTIMA, Oxford OX3 9DU, England

[17] Univ Oxford, Nuffield Dept Clin Med, Div Med Sci, Oxford, England

[18] Univ Bristol, Inst Clin Neurosci, Frenchay Hosp, Dementia Res Grp, Bristol, Avon, England

[19] Univ Leeds, Inst Mol & Cellular Biol, Fac Biol Sci, LIGHT Labs, Leeds, W Yorkshire, England

[20] Salford Royal Natl Hlth Serv NHS Trust, Cerebral Funct Unit, Salford, Lancs, England

[21] Inst Neurol, Dept Mol Neurosci, London WC1N 3BG, England

[22] Inst Neurol, Reta Lilla Weston Labs, London WC1N 3BG, England

[23] UCL, Inst Neurol, Dept Neurodegenerat Dis, London, England

[24] Univ Bonn, Dept Psychiat, D-5300 Bonn, Germany

[25] German Ctr Neurodegenerat Dis, Bonn, Germany

[26] Univ Bonn, Inst Mol Psychiat, D-5300 Bonn, Germany

[27] Univ Gottingen, Dept Psychiat, Gottingen, Germany

[28] Royal Derby Hosp, Dept Psychiat, Derby, England

[29] Univ Med Ctr Hamburg Eppendorf, Inst Primary Med Care, Hamburg, Germany

[30] Charite, Dept Psychiat, Berlin, Germany

[31] Univ Erlangen Nurnberg, Dept Psychiat & Psychotherapy, Nurnberg, Germany

[32] Univ Duisburg Essen, Landschaftsverband Rheinland Hosp Essen, Dept Psychiat & Psychotherapy, Essen, Germany

[33] Klinikum Univ Munchen, Dept Neurol, Munich, Germany

[34] Klinikum Univ Munchen, Inst Stroke & Dementia Res, Munich, Germany

[35] Heidelberg Univ, Dept Geriatr Psychiat, Cent Inst Mental Hlth, Med Fac Mannheim, D-6800 Mannheim, Germany

[36] Goethe Univ Frankfurt, Dept Psychiat Psychsomat Med & Psychotherapy, Frankfurt, Germany

[37] Cardiff Univ, Dept Primary Care & Publ Hlth, Sch Med, Cardiff, S Glam, Wales

[38] Univ Freiburg, Ctr Geriatr Med, Freiburg, Germany

[39] Univ Freiburg, Sect Gerontopsychiat & Neuropsychol, Freiburg, Germany

[40] Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA

[41] Washington Univ, Sch Med, Dept Neurol, St Louis, MO 63110 USA

[42] Washington Univ, Sch Med, Dept Genet, St Louis, MO 63110 USA

[43] Brigham Young Univ, Dept Biol, Provo, UT 84602 USA

[44] Univ Antwerp, Inst Born Bunge, B-2020 Antwerp, Belgium

[45] Univ Antwerp VIB, Dept Mol Genet, Neurodegenerat Brain Dis Grp, B-2610 Antwerp, Belgium

[46] ZiekenhuisNetwerk Antwerpen, Memory Clin, Antwerp, Belgium

[47] ZiekenhuisNetwerk Antwerpen, Dept Neurol, Antwerp, Belgium

[48] UCL, Dept Mental Hlth Sci, London, England

[49] Wellcome Trust Sanger Inst, Cambridge, England

[50] Kings Coll London, MRC, Inst Psychiat, Ctr Neurodegenerat Res,Dept Clin Neurosci, London WC2R 2LS, England

来源：

NATURE GENETICS | 2011年 / 43卷 / 05期

基金：

芬兰科学院; 英国惠康基金; 美国国家卫生研究院; 英国医学研究理事会;

关键词：

GENOME-WIDE ASSOCIATION; RECEPTOR TYROSINE KINASE; IDENTIFIES VARIANTS; GENE-EXPRESSION; CLU; PICALM; CR-1; RISK; LOCI; APOE;

D O I：

10.1038/ng.803

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

We sought to identify new susceptibility loci for Alzheimer's disease through a staged association study (GERAD+) and by testing suggestive loci reported by the Alzheimer's Disease Genetic Consortium (ADGC) in a companion paper. We undertook a combined analysis of four genome-wide association datasets (stage 1) and identified ten newly associated variants with P <= 1 x 10(-5). We tested these variants for association in an independent sample (stage 2). Three SNPs at two loci replicated and showed evidence for association in a further sample (stage 3). Meta-analyses of all data provided compelling evidence that ABCA7 (rs3764650, meta P = 4.5 x 10(-17); including ADGC data, meta P = 5.0 x 10(-21)) and the MS4A gene cluster (rs610932, meta P = 1.8 x 10(-14); including ADGC data, meta P = 1.2 x 10(-16)) are new Alzheimer's disease susceptibility loci. We also found independent evidence for association for three loci reported by the ADGC, which, when combined, showed genome-wide significance: CD2AP (GERAD+, P = 8.0 x 10(-4); including ADGC data, meta P = 8.6 x 10(-9)), CD33 (GERAD+, P = 2.2 x 10(-4); including ADGC data, meta P = 1.6 x 10(-9)) and EPHA1 (GERAD+, P = 3.4 x 10(-4); including ADGC data, meta P = 6.0 x 10(-10)).

引用

页码：429 / +

页数：8

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