Letter

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

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Published online:

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

  • Corrected online 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.

  • Corrected online 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.

Accessions

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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.

Author information

Author notes

    • Denise Harold
    • , Richard Abraham
    •  & Paul Hollingworth

    These authors contributed equally to this work.

Affiliations

  1. Medical Research Council (MRC) Centre for Neuropsychiatric Genetics and Genomics, Department of Psychological Medicine and Neurology, School of Medicine, Cardiff University, Cardiff, UK.

    • Denise Harold
    • , Richard Abraham
    • , Paul Hollingworth
    • , Rebecca Sims
    • , Amy Gerrish
    • , Marian L Hamshere
    • , Jaspreet Singh Pahwa
    • , Valentina Moskvina
    • , Kimberley Dowzell
    • , Amy Williams
    • , Nicola Jones
    • , Charlene Thomas
    • , Alexandra Stretton
    • , Angharad R Morgan
    • , Peter A Holmans
    • , Michael O'Donovan
    • , Michael J Owen
    •  & Julie Williams
  2. National Institute for Health Research Biomedical Research Centre for Mental Health at the South London and Maudsley National Health Service Foundation Trust and Institute of Psychiatry, Kings College, London, UK.

    • Simon Lovestone
  3. Department of Neuroscience, Institute of Psychiatry, Kings College, London, UK.

    • John Powell
    • , Petroula Proitsi
    •  & Michelle K Lupton
  4. Institute of Public Health, St. James Hospital and Trinity College, Dublin, Ireland.

    • Carol Brayne
  5. Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK.

    • David C Rubinsztein
  6. Mercer's Institute for Research on Aging, St. James Hospital and Trinity College, Dublin, Ireland.

    • Michael Gill
    • , Brian Lawlor
    •  & Aoibhinn Lynch
  7. Institute of Genetics, Queen's Medical Centre, University of Nottingham, Nottingham, UK.

    • Kevin Morgan
    •  & Kristelle S Brown
  8. Ageing Group, Centre for Public Health, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, UK.

    • Peter A Passmore
    • , David Craig
    • , Bernadette McGuinness
    •  & Stephen Todd
  9. Division of Clinical Neurosciences, School of Medicine, University of Southampton, Southampton, UK.

    • Clive Holmes
  10. Clinical Neuroscience Research Group, Greater Manchester Neurosciences Centre, University of Manchester, Salford, UK.

    • David Mann
  11. Oxford Project to Investigate Memory and Ageing, University of Oxford, John Radcliffe Hospital, Oxford, UK.

    • A David Smith
  12. Dementia Research Group, University of Bristol Institute of Clinical Neurosciences, Frenchay Hospital, Bristol, UK.

    • Seth Love
    •  & Patrick G Kehoe
  13. Department of Molecular Neuroscience and Reta Lilla Weston Laboratories, Institute of Neurology, London, UK.

    • John Hardy
  14. MRC Prion Unit, UCL Institute of Neurology, London, UK.

    • Simon Mead
    •  & John Collinge
  15. Dementia Research Centre, Department of Neurodegenerative Diseases, UCL Institute of Neurology, London, UK.

    • Nick Fox
    •  & Martin Rossor
  16. Department of Psychiatry, University of Bonn, Bonn, Germany.

    • Wolfgang Maier
    • , Frank Jessen
    • , Britta Schürmann
    •  & Reinhard Heun
  17. Institute of Primary Medical Care, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

    • Hendrik van den Bussche
  18. Department of Psychiatry, Charité Berlin, Berlin, Germany.

    • Isabella Heuser
  19. Department of Psychiatry and Psychotherapy, University of Erlangen-Nürnberg, Erlangen, Germany.

    • Johannes Kornhuber
  20. Landschaftsverband Rheinland-Hospital Essen, Department of Psychiatry and Psychotherapy, University Duisburg-Essen, Essen, Germany.

    • Jens Wiltfang
  21. Institute for Stroke and Dementia Research, Klinikum der Universität München, Munich, Germany.

    • Martin Dichgans
  22. Department of Neurology, Klinikum der Universität München, Munich, Germany.

    • Martin Dichgans
  23. Department of Geriatric Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.

    • Lutz Frölich
  24. Discipline of Psychiatry, School of Medicine and Trinity College Institute of Neuroscience, Laboratory of Neuroimaging & Biomarker Research, Trinity College, University of Dublin, Dublin, Ireland.

    • Harald Hampel
  25. Alzheimer Memorial Center and Geriatric Psychiatry Branch, Department of Psychiatry, Ludwig-Maximilian University, Munich, Germany.

    • Harald Hampel
    •  & Dan Rujescu
  26. Centre for Geriatric Medicine and Section of Gerontopsychiatry and Neuropsychology, Medical School, University of Freiburg, Freiburg, Germany.

    • Michael Hüll
  27. Departments of Psychiatry, Neurology and Genetics, Washington University School of Medicine, St. Louis, Missouri, USA.

    • Alison M Goate
    • , Carlos Cruchaga
    • , Petra Nowotny
    • , John C Morris
    •  & Kevin Mayo
  28. Department of Biology, Brigham Young University, Provo, Utah, USA.

    • John S K Kauwe
  29. Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB, Antwerpen, Belgium.

    • Kristel Sleegers
    • , Karolien Bettens
    •  & Christine Van Broeckhoven
  30. Institute Born-Bunge and University of Antwerp, Antwerpen, Belgium.

    • Kristel Sleegers
    • , Karolien Bettens
    • , Sebastiaan Engelborghs
    • , Peter P De Deyn
    •  & Christine Van Broeckhoven
  31. Memory Clinic and Department of Neurology, Ziekenhuis Netwerk Antwerpen Middelheim, Antwerpen, Belgium.

    • Sebastiaan Engelborghs
    •  & Peter P De Deyn
  32. Department of Mental Health Sciences, University College London, London, UK.

    • Gill Livingston
    • , Nicholas J Bass
    • , Hugh Gurling
    •  & Andrew McQuillin
  33. The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK.

    • Rhian Gwilliam
    •  & Panagiotis Deloukas
  34. MRC Centre for Neurodegeneration Research, Department of Clinical Neuroscience, King's College London, Institute of Psychiatry, London, UK.

    • Ammar Al-Chalabi
    •  & Christopher E Shaw
  35. Third Department of Neurology, Aristotle University of Thessaloniki, Thessaloniki, Greece.

    • Magda Tsolaki
  36. Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA.

    • Andrew B Singleton
    •  & Rita Guerreiro
  37. Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany.

    • Thomas W Mühleisen
    •  & Markus M Nöthen
  38. Institute of Human Genetics, University of Bonn, Bonn, Germany.

    • Thomas W Mühleisen
    •  & Markus M Nöthen
  39. Institute for Medical Informatics, Biometry and Epidemiology, University Hospital of Essen, University Duisburg-Essen, Essen, Germany.

    • Susanne Moebus
    •  & Karl-Heinz Jöckel
  40. Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.

    • Norman Klopp
    •  & H-Erich Wichmann
  41. Institute of Medical Informatics, Biometry and Epidemiology, Ludwig-Maximilians-Universität, Munich, Germany.

    • H-Erich Wichmann
  42. Klinikum Grosshadern, Munich, Germany.

    • H-Erich Wichmann
  43. Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, Florida, USA.

    • Minerva M Carrasquillo
    •  & Steven G Younkin
  44. Division of Biomedical Statistics and Informatics, Mayo Clinic and Mayo Foundation, Rochester, Minnesota, USA.

    • V Shane Pankratz

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Competing interests

The authors have applied for a patent based on the results of this research.

Corresponding authors

Correspondence to Michael J Owen or Julie Williams.

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Tables 1,3 and 4, Supplementary Note

Excel files

  1. 1.

    Supplementary Table 2

    SNPs showing association with AD (P ≤ 1×10−3) in the GWAS.

  2. 2.

    Supplementary Table 5

    Results for SNPs highlighted by previous GWA studies in our sample

  3. 3.

    Supplementary Table 6

    SNPs showing association with AD (P ≤ 1×10−3) in the APOE-ε4 positive sample

  4. 4.

    Supplementary Table 7

    SNPs showing association with AD (P ≤ 1×10−3) in the APOE-ε4 negative sample