Abstract
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 × 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 × 10 9) and 5′ to the PICALM gene (rs3851179, P = 1.9 × 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 × 10 10, odds ratio = 0.86; rs3851179, P = 1.3 × 10 9, odds ratio = 0.86).
Original language | English |
---|---|
Pages (from-to) | 1088-1093 |
Number of pages | 6 |
Journal | Nature Genetics |
Volume | 41 |
Issue number | 10 |
DOIs | |
State | Published - Oct 1 2009 |
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In: Nature Genetics, Vol. 41, No. 10, 01.10.2009, p. 1088-1093.
Research output: Contribution to journal › Article › peer-review
TY - JOUR
T1 - Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease
AU - Harold, Denise
AU - Abraham, Richard
AU - Hollingworth, Paul
AU - Sims, Rebecca
AU - Gerrish, Amy
AU - Hamshere, Marian L.
AU - Pahwa, Jaspreet Singh
AU - Moskvina, Valentina
AU - Dowzell, Kimberley
AU - Williams, Amy
AU - Jones, Nicola
AU - Thomas, Charlene
AU - Stretton, Alexandra
AU - Morgan, Angharad R.
AU - Lovestone, Simon
AU - Powell, John
AU - Proitsi, Petroula
AU - Lupton, Michelle K.
AU - Brayne, Carol
AU - Rubinsztein, David C.
AU - Gill, Michael
AU - Lawlor, Brian
AU - Lynch, Aoibhinn
AU - Morgan, Kevin
AU - Brown, Kristelle S.
AU - Passmore, Peter A.
AU - Craig, David
AU - McGuinness, Bernadette
AU - Todd, Stephen
AU - Holmes, Clive
AU - Mann, David
AU - Smith, A. David
AU - Love, Seth
AU - Kehoe, Patrick G.
AU - Hardy, John
AU - Mead, Simon
AU - Fox, Nick
AU - Rossor, Martin
AU - Collinge, John
AU - Maier, Wolfgang
AU - Jessen, Frank
AU - Schürmann, Britta
AU - Heun, Reinhard
AU - Van Den Bussche, Hendrik
AU - Heuser, Isabella
AU - Kornhuber, Johannes
AU - Wiltfang, Jens
AU - Dichgans, Martin
AU - Frölich, Lutz
AU - Hampel, Harald
AU - Hüll, Michael
AU - Rujescu, Dan
AU - Goate, Alison M.
AU - Kauwe, John S.K.
AU - Cruchaga, Carlos
AU - Nowotny, Petra
AU - Morris, John C.
AU - Mayo, Kevin
AU - Sleegers, Kristel
AU - Bettens, Karolien
AU - Engelborghs, Sebastiaan
AU - Van Broeckhoven, Christine
AU - Livingston, Gill
AU - Bass, Nicholas J.
AU - Gurling, Hugh
AU - McQuillin, Andrew
AU - Gwilliam, Rhian
AU - Deloukas, Panagiotis
AU - Al-Chalabi, Ammar
AU - Shaw, Christopher E.
AU - Tsolaki, Magda
AU - Singleton, Andrew B.
AU - Guerreiro, Rita
AU - Mühleisen, Thomas W.
AU - Nöthen, Markus M.
AU - Moebus, Susanne
AU - Jöckel, Karl Heinz
AU - Klopp, Norman
AU - Wichmann, H. Erich
AU - Carrasquillo, Minerva M.
AU - Pankratz, V. Shane
AU - Holmans, Peter A.
AU - O'Donovan, Michael
AU - Owen, Michael J.
AU - Williams, Julie
N1 - Funding Information: We thank the individuals and families who took part in this research. Cardiff University was supported by the Wellcome Trust, Medical Research Council (MRC, UK), Alzheimer’s Research Trust (ART) and the Welsh Assembly Government. ART supported sample collections at the Institute of Psychiatry, the South West Dementia Bank and the Universities of Cambridge, Nottingham, Manchester and Belfast. The Belfast group acknowledges support from the Alzheimer’s Society, Ulster Garden Villages, Northern Ireland Research and Development Office and the Royal College of Physicians–Dunhill Medical Trust. The MRC and Mercer’s Institute for Research on Ageing supported the Trinity College group. The South West Dementia Brain Bank acknowledges support from Bristol Research into Alzheimer’s and Care of the Elderly. The Charles Wolfson Charitable Trust supported the Oxford Project to Investigate Memory and Ageing (OPTIMA) group. A.A.-C. and C.E.S. thank the Motor Neurone Disease Association and MRC for support. D.C.R. is a Wellcome Trust Senior Clinical Research Fellow. Washington University was funded by US National Institutes of Health (NIH) grants, the Barnes Jewish Foundation and the Charles and Joanne Knight Alzheimer’s Research Initiative. The Mayo GWAS was supported by NIH grants, the Robert and Clarice Smith and Abigail Van Buren AD Research Program, and the Palumbo Professorship in AD Research. Patient recruitment for the MRC Prion Unit/University College London Department of Neurodegenerative Disease collection was supported by the UCL Hospital/UCL Biomedical Centre. London and the South East Region (LASER)-AD was funded by Lundbeck. The Bonn group was supported by the German Federal Ministry of Education and Research (BMBF), Competence Network Dementia and Competence Network Degenerative Dementia, and by the Alfried Krupp von Bohlen und Halbach-Stiftung. The Kooperative gesundheitsforschung in der region Augsburg (KORA) F4 studies were financed by Helmholtz Zentrum München, the German Research Center for Environmental Health, BMBF, the German National Genome Research Network and the Munich Center of Health Sciences. The Heinz Nixdorf Recall cohort was funded by the Heinz Nixdorf Foundation (G. Schmidt, chairman) and BMBF. Coriell Cell Repositories is supported by the US National Institute of Neurological Disorders and Stroke and the Intramural Research Program (IRP) of the National Institute on Aging (NIA). Work on this sample was supported in part by the IRP of the NIA, National Institutes of Health, Department of Health and Human Services; Z01 AG000950-06. We acknowledge use of DNA from the 1958 Birth Cohort collection, funded by the MRC and the Wellcome Trust, which was genotyped by the Wellcome Trust Case Control Consortium and the Type-1 Diabetes Genetics Consortium, sponsored by the US National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Allergy and Infectious Diseases, National Human Genome Research Institute, National Institute of Child Health and Human Development and Juvenile Diabetes Research Foundation International. The Antwerp site was supported by the VIB Genetic Service Facility, the Biobank of the Institute Born-Bunge, the Special Research Fund of the University of Antwerp, the Fund for Scientific Research-Flanders, the Foundation for Alzheimer Research and the Interuniversity Attraction Poles program P6/43 of the Belgian Federal Science Policy Office. K.S. is a postdoctoral fellow and K.B. a PhD fellow (Fund for Scientific Research-Flanders). We thank R. Brown, J. Landers, D. Warden, D. Lehmann, N. Leigh, J. Uphill, J. Beck, T. Campbell, S. Klier, G. Adamson, J. Wyatt, M.L. Perez, T. Meitinger, P. Lichtner, G. Eckstein, N. Graff-Radford, R. Petersen, D. Dickson, G. Fischer, H. Bickel, H. Jahn, H. Kaduszkiewicz, C. Luckhaus, S. Riedel-Heller, S. Wolf, S. Weyerer, the Helmholtz Zentrum München genotyping staff, E. Reiman, TGEN and the NIMH AD Genetics Initiative. We thank Advanced Research Computing @Cardiff (ARCCA), which facilitated data analysis.
PY - 2009/10/1
Y1 - 2009/10/1
N2 - 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 × 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 × 10 9) and 5′ to the PICALM gene (rs3851179, P = 1.9 × 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 × 10 10, odds ratio = 0.86; rs3851179, P = 1.3 × 10 9, odds ratio = 0.86).
AB - 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 × 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 × 10 9) and 5′ to the PICALM gene (rs3851179, P = 1.9 × 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 × 10 10, odds ratio = 0.86; rs3851179, P = 1.3 × 10 9, odds ratio = 0.86).
UR - http://www.scopus.com/inward/record.url?scp=70349558522&partnerID=8YFLogxK
U2 - 10.1038/ng.440
DO - 10.1038/ng.440
M3 - Article
C2 - 19734902
AN - SCOPUS:70349558522
SN - 1061-4036
VL - 41
SP - 1088
EP - 1093
JO - Nature Genetics
JF - Nature Genetics
IS - 10
ER -