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

  • ️Williams, Julie
  • ️Sun Sep 06 2009

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  • 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.

Author information

Author notes

  1. Denise Harold, Richard Abraham and Paul Hollingworth: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Psychological Medicine and Neurology, Medical Research Council (MRC) Centre for Neuropsychiatric Genetics and Genomics, 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. Department of Neurodegenerative Diseases, Dementia Research Centre, 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. Department of Psychiatry and Psychotherapy, Landschaftsverband Rheinland-Hospital Essen, 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. Department of Psychiatry, Alzheimer Memorial Center and Geriatric Psychiatry Branch, 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. Department of Molecular Genetics, Neurodegenerative Brain Diseases Group, 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. Department of Clinical Neuroscience, MRC Centre for Neurodegeneration Research, 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

Authors

  1. Denise Harold

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  2. Richard Abraham

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  3. Paul Hollingworth

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  4. Rebecca Sims

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  5. Amy Gerrish

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  6. Marian L Hamshere

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  7. Jaspreet Singh Pahwa

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  8. Valentina Moskvina

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  9. Kimberley Dowzell

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  10. Amy Williams

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  11. Nicola Jones

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  12. Charlene Thomas

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  13. Alexandra Stretton

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  14. Angharad R Morgan

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  15. Simon Lovestone

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  16. John Powell

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  17. Petroula Proitsi

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  18. Michelle K Lupton

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  19. Carol Brayne

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  20. David C Rubinsztein

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  21. Michael Gill

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  22. Brian Lawlor

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  23. Aoibhinn Lynch

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  24. Kevin Morgan

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  25. Kristelle S Brown

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  26. Peter A Passmore

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  27. David Craig

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  28. Bernadette McGuinness

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  29. Stephen Todd

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  30. Clive Holmes

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  31. David Mann

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  32. A David Smith

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  33. Seth Love

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  34. Patrick G Kehoe

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  35. John Hardy

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  36. Simon Mead

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  37. Nick Fox

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  38. Martin Rossor

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  39. John Collinge

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  43. Reinhard Heun

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  44. Hendrik van den Bussche

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  45. Isabella Heuser

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  46. Johannes Kornhuber

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  47. Jens Wiltfang

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  48. Martin Dichgans

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  49. Lutz Frölich

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  50. Harald Hampel

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  51. Michael Hüll

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  52. Dan Rujescu

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  53. Alison M Goate

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Contributions

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.

Corresponding authors

Correspondence to Michael J Owen or Julie Williams.

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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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  • Received: 28 April 2009

  • Accepted: 31 July 2009

  • Published: 06 September 2009

  • Issue Date: October 2009

  • DOI: https://doi.org/10.1038/ng.440