Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease

被引：2147

作者：

Harold, Denise ^{[1
]}

Abraham, Richard ^{[1
]}

Hollingworth, Paul ^{[1
]}

Sims, Rebecca ^{[1
]}

Gerrish, Amy ^{[1
]}

Hamshere, Marian L. ^{[1
]}

Pahwa, Jaspreet Singh ^{[1
]}

Moskvina, Valentina ^{[1
]}

Dowzell, Kimberley ^{[1
]}

Williams, Amy ^{[1
]}

Jones, Nicola ^{[1
]}

Thomas, Charlene ^{[1
]}

Stretton, Alexandra ^{[1
]}

Morgan, Angharad R. ^{[1
]}

Lovestone, Simon ^{[2
]}

Powell, John ^{[3
]}

Proitsi, Petroula ^{[3
]}

Lupton, Michelle K. ^{[3
]}

Brayne, Carol ^{[4
]}

Rubinsztein, David C. ^{[5
]}

Gill, Michael ^{[6
,7
]}

Lawlor, Brian ^{[6
,7
]}

Lynch, Aoibhinn ^{[6
,7
]}

Morgan, Kevin ^{[8
]}

Brown, Kristelle S. ^{[8
]}

Passmore, Peter A. ^{[9
]}

Craig, David ^{[9
]}

McGuinness, Bernadette ^{[9
]}

Todd, Stephen ^{[9
]}

Holmes, Clive ^{[10
]}

Mann, David ^{[11
]}

Smith, A. David ^{[12
]}

Love, Seth ^{[13
]}

Kehoe, Patrick G. ^{[13
]}

Hardy, John ^{[14
,15
]}

Mead, Simon ^{[16
]}

Fox, Nick ^{[17
]}

Rossor, Martin ^{[17
]}

Collinge, John ^{[16
]}

Maier, Wolfgang ^{[18
]}

Jessen, Frank ^{[18
]}

Schuermann, Britta ^{[18
]}

van den Bussche, Hendrik ^{[19
]}

Heuser, Isabella ^{[20
]}

Kornhuber, Johannes ^{[21
]}

Wiltfang, Jens ^{[22
]}

Dichgans, Martin ^{[23
,24
]}

Froelich, Lutz ^{[25
]}

Hampel, Harald ^{[26
,27
,28
,29
]}

Huell, Michael ^{[30
,31
]}

机构：

[1] Cardiff Univ, MRC, Ctr Neuropsychiat Genet & Genom, Dept Psychol Med & Neurol,Sch Med, Cardiff, S Glam, Wales

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

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

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

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

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

[7] Trinity Coll Dublin, Dublin, Ireland

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

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

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

[11] Univ Manchester, Clin Neurosci Res Grp, Greater Manchester Neurosci Ctr, Salford, Lancs, England

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

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

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

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

[16] UCL Inst Neurol, MRC, Prion Unit, London, England

[17] UCL Inst Neurol, Dementia Res Ctr, Dept Neurodegenerat Dis, London, England

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

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

[20] Charite, Dept Psychiat, Berlin, Germany

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

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

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

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

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

[26] Univ Dublin Trinity Coll, Discipline Psychiat, Sch Med, Dublin 2, Ireland

[27] Univ Dublin Trinity Coll, Inst Neurosci, Lab Neuroimaging & Biomarker Res, Dublin 2, Ireland

[28] Univ Munich, Dept Psychiat, Alzheimer Mem Ctr, D-8000 Munich, Germany

[29] Univ Munich, Dept Psychiat, Geriatr Psychiat Branch, D-8000 Munich, Germany

[30] Univ Freiburg, Ctr Geriatr Med, Sch Med, Freiburg, Germany

[31] Univ Freiburg, Sect Gerontopsychiat & Neuropsychol, Sch Med, Freiburg, Germany

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

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

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

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

[36] VIB, Neurodegenerat Brain Dis Grp, Dept Mol Genet, Antwerp, Belgium

[37] Inst Born Bunge, Antwerp, Belgium

[38] Univ Antwerp, B-2020 Antwerp, Belgium

[39] Ziekenhuis Netwerk Antwerpen Middelheim, Memory Clin, Antwerp, Belgium

[40] Ziekenhuis Netwerk Antwerpen Middelheim, Dept Neurol, Antwerp, Belgium

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

[42] Wellcome Trust Sanger Inst, Cambridge, England

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

[44] Aristotle Univ Thessaloniki, Dept Neurol 3, GR-54006 Thessaloniki, Greece

[45] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA

[46] Univ Bonn, Dept Genom, Life & Brain Ctr, D-5300 Bonn, Germany

[47] Univ Bonn, Inst Human Genet, D-5300 Bonn, Germany

[48] Univ Duisburg Essen, Univ Hosp Essen, Inst Med Informat Biometry & Epidemiol, Essen, Germany

[49] German Res Ctr Environm Hlth, Inst Epidemiol, Helmholtz Zentrum Munchen, Neuherberg, Germany

[50] Univ Munich, Inst Med Informat Biometry & Epidemiol, Munich, Germany

来源：

NATURE GENETICS | 2009年 / 41卷 / 10期

基金：

英国惠康基金; 英国医学研究理事会; 美国国家卫生研究院;

关键词：

SINGLE-NUCLEOTIDE POLYMORPHISMS; AMYLOID-PRECURSOR-PROTEIN; APOLIPOPROTEIN-J; BETA-PROTEIN; LARGE-SCALE; SUSCEPTIBILITY LOCI; MOUSE MODEL; IN-VITRO; CLUSTERIN; BRAIN;

D O I：

10.1038/ng.440

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

We undertook a two-stage genome-wide association study (GWAS) of Alzheimer's disease (AD) involving over 16,000 individuals, the most powerful AD GWAS to date. In stage 1 (3,941 cases and 7,848 controls), we replicated the established association with the apolipoprotein E (APOE) locus (most significant SNP, rs2075650, P = 1.8 x 10(-157)) and observed genome-wide significant association with SNPs at two loci not previously associated with the disease: at the CLU (also known as APOJ) gene (rs11136000, P = 1.4 x 10(-9)) and 5. to the PICALM gene (rs3851179, P = 1.9 x 10(-8)). These associations were replicated in stage 2 (2,023 cases and 2,340 controls), producing compelling evidence for association with Alzheimer's disease in the combined dataset (rs11136000, P = 8.5 x 10(-10), odds ratio = 0.86; rs3851179, P = 1.3 x 10(-9), odds ratio = 0.86).

引用

页码：1088 / U61

页数：8

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