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).
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Change history
28 September 2009
NOTE: In the version of this article initially published, the name of the first author of reference 12 was stated incorrectly in the reference list. The correct reference is: “Lambert, J.-C. et al. Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer's disease. Nat. Genet. advance online publication, doi:10.1038/ng.439 (6 September 2009).” The error has been corrected in the HTML and PDF versions of the article.
09 May 2013
In the version of this article initially published, Reinhard Heun was not included in the author list. This has been corrected in the HTML and PDF versions of the article.
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Acknowledgements
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.
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J. Williams, M.J.O. and M.O. directed this study, assisted by R.A., P.H. and P.A.H. D.H. and J. Williams took primary responsibility for drafting the manuscript assisted by R.A., P.H., R.S., A.G., M.O. and M.J.O. J. Williams, R.A., P.H., R.S., A.G., K.D., A.W., N.J., C.T., A.S., A.R.M., S. Lovestone, J.P., P.P., M.K.L., C.B., D.C.R., M.G., B.L., A.L., K. Morgan, K.S.B., P.A.P., D.C., B.M., S.T., C.H., D.M., A.D.S., S. Love, P.G.K., J.H., S. Mead, N.F., M.R., J.C., W.M., F.J., B.S., R.H., H.v.d.B., I.H., J.K., J. Wiltfang, M.D., L.F., A.M.G., J.S.K.K., C.C., P.N., J.C.M., K. Mayo, G.L., N.J.B., H.G. and A.M. contributed towards clinical sample collection, ascertainment, diagnosis and preparation of samples from the '610 group' from the stage 1 'discovery sample' and in some cases also provided stage 2 'follow up' samples. R.A. and P.H. were responsible for the coordination, collection, transit and selection of samples for genotyping from the '610 group'. R. Gwilliam and P.D. were responsible for procedures related to genotyping the 610 group on the Illumina platform. A.A.-C., C.E.S., A.B.S., R. Guerreiro, T.W.M., M.M.N., S.M., K.-H.J., N.K., H.-E.W., M.M.C., V.S.P., S.G.Y., H.H., D.R. and M.H. were involved in clinical sample collection, ascertainment, diagnosis, preparation of samples and genotyping of 'collaborative samples' included in Stage 1 (i.e. samples other than the '610 group'). K.S., K.B., S.E., P.P.D.D., C.v.B. and M.T. contributed towards sample collection, diagnosis and preparation of case-control material for the stage 2 'replication sample'. Replication genotyping was coordinated and performed by R.A., assisted by R.S. and A.G. and J.S.P. developed the database for the GWA project in which the data were stored, under the supervision of J. Williams. D.H. completed statistical quality control and produced association statistics, under the supervision of J. Williams, M.L.H., V.M. and P.A.H. All authors discussed the results and approved the manuscript.
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Supplementary Text and Figures
Supplementary Tables 1,3 and 4, Supplementary Note (PDF 544 kb)
Supplementary Table 2
SNPs showing association with AD (P ≤ 1×10−3) in the GWAS. (XLS 258 kb)
Supplementary Table 5
Results for SNPs highlighted by previous GWA studies in our sample (XLS 37 kb)
Supplementary Table 6
SNPs showing association with AD (P ≤ 1×10−3) in the APOE-ε4 positive sample (XLS 76 kb)
Supplementary Table 7
SNPs showing association with AD (P ≤ 1×10−3) in the APOE-ε4 negative sample (XLS 76 kb)
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Harold, D., Abraham, R., Hollingworth, P. et al. Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease. Nat Genet 41, 1088–1093 (2009). https://doi.org/10.1038/ng.440
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DOI: https://doi.org/10.1038/ng.440
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