Letter abstract

Nature Genetics 41, 1088 - 1093 (2009)
Published online: 6 September 2009 | Corrected online: 28 September 2009 | Corrected online: 9 May 2013 | doi:10.1038/ng.440

There is an Erratum (October 2009) associated with this Letter.

There is a Corrigendum (June 2013) associated with this Letter.

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

Denise Harold1,45, Richard Abraham1,45, Paul Hollingworth1,45, Rebecca Sims1, Amy Gerrish1, Marian L Hamshere1, Jaspreet Singh Pahwa1, Valentina Moskvina1, Kimberley Dowzell1, Amy Williams1, Nicola Jones1, Charlene Thomas1, Alexandra Stretton1, Angharad R Morgan1, Simon Lovestone2, John Powell3, Petroula Proitsi3, Michelle K Lupton3, Carol Brayne4, David C Rubinsztein5, Michael Gill6, Brian Lawlor6, Aoibhinn Lynch6, Kevin Morgan7, Kristelle S Brown7, Peter A Passmore8, David Craig8, Bernadette McGuinness8, Stephen Todd8, Clive Holmes9, David Mann10, A David Smith11, Seth Love12, Patrick G Kehoe12, John Hardy13, Simon Mead14, Nick Fox15, Martin Rossor15, John Collinge14, Wolfgang Maier16, Frank Jessen16, Britta Schürmann16, Reinhard Heun16, Hendrik van den Bussche17, Isabella Heuser18, Johannes Kornhuber19, Jens Wiltfang20, Martin Dichgans21,22, Lutz Frölich23, Harald Hampel24,25, Michael Hüll26, Dan Rujescu25, Alison M Goate27, John S K Kauwe28, Carlos Cruchaga27, Petra Nowotny27, John C Morris27, Kevin Mayo27, Kristel Sleegers29,30, Karolien Bettens29,30, Sebastiaan Engelborghs30,31, Peter P De Deyn30,31, Christine Van Broeckhoven29,30, Gill Livingston32, Nicholas J Bass32, Hugh Gurling32, Andrew McQuillin32, Rhian Gwilliam33, Panagiotis Deloukas33, Ammar Al-Chalabi34, Christopher E Shaw34, Magda Tsolaki35, Andrew B Singleton36, Rita Guerreiro36, Thomas W Mühleisen37,38, Markus M Nöthen37,38, Susanne Moebus39, Karl-Heinz Jöckel39, Norman Klopp40, H-Erich Wichmann40,41,42, Minerva M Carrasquillo43, V Shane Pankratz44, Steven G Younkin43, Peter A Holmans1, Michael O'Donovan1, Michael J Owen1 & Julie Williams1


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).

  1. Medical Research Council (MRC) Centre for Neuropsychiatric Genetics and Genomics, Department of Psychological Medicine and Neurology, School of Medicine, Cardiff University, Cardiff, UK.
  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.
  3. Department of Neuroscience, Institute of Psychiatry, Kings College, London, UK.
  4. Institute of Public Health, St. James Hospital and Trinity College, Dublin, Ireland.
  5. Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK.
  6. Mercer's Institute for Research on Aging, St. James Hospital and Trinity College, Dublin, Ireland.
  7. Institute of Genetics, Queen's Medical Centre, University of Nottingham, Nottingham, UK.
  8. Ageing Group, Centre for Public Health, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, UK.
  9. Division of Clinical Neurosciences, School of Medicine, University of Southampton, Southampton, UK.
  10. Clinical Neuroscience Research Group, Greater Manchester Neurosciences Centre, University of Manchester, Salford, UK.
  11. Oxford Project to Investigate Memory and Ageing, University of Oxford, John Radcliffe Hospital, Oxford, UK.
  12. Dementia Research Group, University of Bristol Institute of Clinical Neurosciences, Frenchay Hospital, Bristol, UK.
  13. Department of Molecular Neuroscience and Reta Lilla Weston Laboratories, Institute of Neurology, London, UK.
  14. MRC Prion Unit, UCL Institute of Neurology, London, UK.
  15. Dementia Research Centre, Department of Neurodegenerative Diseases, UCL Institute of Neurology, London, UK.
  16. Department of Psychiatry, University of Bonn, Bonn, Germany.
  17. Institute of Primary Medical Care, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
  18. Department of Psychiatry, Charité Berlin, Berlin, Germany.
  19. Department of Psychiatry and Psychotherapy, University of Erlangen-Nürnberg, Erlangen, Germany.
  20. Landschaftsverband Rheinland-Hospital Essen, Department of Psychiatry and Psychotherapy, University Duisburg-Essen, Essen, Germany.
  21. Institute for Stroke and Dementia Research, Klinikum der Universität München, Munich, Germany.
  22. Department of Neurology, Klinikum der Universität München, Munich, Germany.
  23. Department of Geriatric Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
  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.
  25. Alzheimer Memorial Center and Geriatric Psychiatry Branch, Department of Psychiatry, Ludwig-Maximilian University, Munich, Germany.
  26. Centre for Geriatric Medicine and Section of Gerontopsychiatry and Neuropsychology, Medical School, University of Freiburg, Freiburg, Germany.
  27. Departments of Psychiatry, Neurology and Genetics, Washington University School of Medicine, St. Louis, Missouri, USA.
  28. Department of Biology, Brigham Young University, Provo, Utah, USA.
  29. Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB, Antwerpen, Belgium.
  30. Institute Born-Bunge and University of Antwerp, Antwerpen, Belgium.
  31. Memory Clinic and Department of Neurology, Ziekenhuis Netwerk Antwerpen Middelheim, Antwerpen, Belgium.
  32. Department of Mental Health Sciences, University College London, London, UK.
  33. The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK.
  34. MRC Centre for Neurodegeneration Research, Department of Clinical Neuroscience, King's College London, Institute of Psychiatry, London, UK.
  35. Third Department of Neurology, Aristotle University of Thessaloniki, Thessaloniki, Greece.
  36. Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA.
  37. Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany.
  38. Institute of Human Genetics, University of Bonn, Bonn, Germany.
  39. Institute for Medical Informatics, Biometry and Epidemiology, University Hospital of Essen, University Duisburg-Essen, Essen, Germany.
  40. Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
  41. Institute of Medical Informatics, Biometry and Epidemiology, Ludwig-Maximilians-Universität, Munich, Germany.
  42. Klinikum Grosshadern, Munich, Germany.
  43. Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, Florida, USA.
  44. Division of Biomedical Statistics and Informatics, Mayo Clinic and Mayo Foundation, Rochester, Minnesota, USA.
  45. These authors contributed equally to this work.

Correspondence to: Julie Williams1 e-mail: williamsj@cardiff.ac.uk

Correspondence to: Michael J Owen1 e-mail: owenmj@cardiff.ac.uk

* 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.

** 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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