Advertisement
Research Article

Genetic Evidence Implicates the Immune System and Cholesterol Metabolism in the Aetiology of Alzheimer's Disease

  • Lesley Jones equal contributor,

    equal contributor Contributed equally to this work with: Lesley Jones, Peter A. Holmans

    Affiliation: Medical Research Council (MRC) Centre for Neuropsychiatric Genetics and Genomics, Department of Psychological Medicine and Neurology, School of Medicine, Cardiff University, Cardiff, United Kingdom

    X
  • Peter A. Holmans equal contributor,

    equal contributor Contributed equally to this work with: Lesley Jones, Peter A. Holmans

    Affiliation: Medical Research Council (MRC) Centre for Neuropsychiatric Genetics and Genomics, Department of Psychological Medicine and Neurology, School of Medicine, Cardiff University, Cardiff, United Kingdom

    X
  • Marian L. Hamshere,

    Affiliation: Medical Research Council (MRC) Centre for Neuropsychiatric Genetics and Genomics, Department of Psychological Medicine and Neurology, School of Medicine, Cardiff University, Cardiff, United Kingdom

    X
  • Denise Harold,

    Affiliation: Medical Research Council (MRC) Centre for Neuropsychiatric Genetics and Genomics, Department of Psychological Medicine and Neurology, School of Medicine, Cardiff University, Cardiff, United Kingdom

    X
  • Valentina Moskvina,

    Affiliation: Medical Research Council (MRC) Centre for Neuropsychiatric Genetics and Genomics, Department of Psychological Medicine and Neurology, School of Medicine, Cardiff University, Cardiff, United Kingdom

    X
  • Dobril Ivanov,

    Affiliation: Medical Research Council (MRC) Centre for Neuropsychiatric Genetics and Genomics, Department of Psychological Medicine and Neurology, School of Medicine, Cardiff University, Cardiff, United Kingdom

    X
  • Andrew Pocklington,

    Affiliation: Medical Research Council (MRC) Centre for Neuropsychiatric Genetics and Genomics, Department of Psychological Medicine and Neurology, School of Medicine, Cardiff University, Cardiff, United Kingdom

    X
  • Richard Abraham,

    Affiliation: Medical Research Council (MRC) Centre for Neuropsychiatric Genetics and Genomics, Department of Psychological Medicine and Neurology, School of Medicine, Cardiff University, Cardiff, United Kingdom

    X
  • Paul Hollingworth,

    Affiliation: Medical Research Council (MRC) Centre for Neuropsychiatric Genetics and Genomics, Department of Psychological Medicine and Neurology, School of Medicine, Cardiff University, Cardiff, United Kingdom

    X
  • Rebecca Sims,

    Affiliation: Medical Research Council (MRC) Centre for Neuropsychiatric Genetics and Genomics, Department of Psychological Medicine and Neurology, School of Medicine, Cardiff University, Cardiff, United Kingdom

    X
  • Amy Gerrish,

    Affiliation: Medical Research Council (MRC) Centre for Neuropsychiatric Genetics and Genomics, Department of Psychological Medicine and Neurology, School of Medicine, Cardiff University, Cardiff, United Kingdom

    X
  • Jaspreet Singh Pahwa,

    Affiliation: Medical Research Council (MRC) Centre for Neuropsychiatric Genetics and Genomics, Department of Psychological Medicine and Neurology, School of Medicine, Cardiff University, Cardiff, United Kingdom

    X
  • Nicola Jones,

    Affiliation: Medical Research Council (MRC) Centre for Neuropsychiatric Genetics and Genomics, Department of Psychological Medicine and Neurology, School of Medicine, Cardiff University, Cardiff, United Kingdom

    X
  • Alexandra Stretton,

    Affiliation: Medical Research Council (MRC) Centre for Neuropsychiatric Genetics and Genomics, Department of Psychological Medicine and Neurology, School of Medicine, Cardiff University, Cardiff, United Kingdom

    X
  • Angharad R. Morgan,

    Affiliation: Medical Research Council (MRC) Centre for Neuropsychiatric Genetics and Genomics, Department of Psychological Medicine and Neurology, School of Medicine, Cardiff University, Cardiff, United Kingdom

    X
  • Simon Lovestone,

    Affiliation: 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, United Kingdom

    X
  • John Powell,

    Affiliation: Department of Neuroscience, Institute of Psychiatry, Kings College, London, United Kingdom

    X
  • Petroula Proitsi,

    Affiliation: Department of Neuroscience, Institute of Psychiatry, Kings College, London, United Kingdom

    X
  • Michelle K. Lupton,

    Affiliation: Department of Neuroscience, Institute of Psychiatry, Kings College, London, United Kingdom

    X
  • Carol Brayne,

    Affiliation: Institute of Public Health, University of Cambridge, Cambridge, United Kingdom

    X
  • David C. Rubinsztein,

    Affiliation: Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom

    X
  • Michael Gill,

    Affiliation: Mercer's Institute for Research on Aging, St. James Hospital and Trinity College, Dublin, Ireland

    X
  • Brian Lawlor,

    Affiliation: Mercer's Institute for Research on Aging, St. James Hospital and Trinity College, Dublin, Ireland

    X
  • Aoibhinn Lynch,

    Affiliation: Mercer's Institute for Research on Aging, St. James Hospital and Trinity College, Dublin, Ireland

    X
  • Kevin Morgan,

    Affiliation: Institute of Genetics, Queen's Medical Centre, University of Nottingham, Nottingham, United Kingdom

    X
  • Kristelle S. Brown,

    Affiliation: Institute of Genetics, Queen's Medical Centre, University of Nottingham, Nottingham, United Kingdom

    X
  • Peter A. Passmore,

    Affiliation: Ageing Group, Centre for Public Health, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, United Kingdom

    X
  • David Craig,

    Affiliation: Ageing Group, Centre for Public Health, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, United Kingdom

    X
  • Bernadette McGuinness,

    Affiliation: Ageing Group, Centre for Public Health, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, United Kingdom

    X
  • Stephen Todd,

    Affiliation: Ageing Group, Centre for Public Health, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, United Kingdom

    X
  • Clive Holmes,

    Affiliation: Division of Clinical Neurosciences, School of Medicine, University of Southampton, Southampton, United Kingdom

    X
  • David Mann,

    Affiliation: Clinical Neuroscience Research Group, Greater Manchester Neurosciences Centre, University of Manchester, Salford, United Kingdom

    X
  • A. David Smith,

    Affiliation: Oxford Project to Investigate Memory and Ageing, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom

    X
  • Seth Love,

    Affiliation: Dementia Research Group, University of Bristol Institute of Clinical Neurosciences, Frenchay Hospital, Bristol, United Kingdom

    X
  • Patrick G. Kehoe,

    Affiliation: Dementia Research Group, University of Bristol Institute of Clinical Neurosciences, Frenchay Hospital, Bristol, United Kingdom

    X
  • Simon Mead,

    Affiliation: MRC Prion Unit, Department of Neurodegenerative Diseases, UCL Institute of Neurology, London, United Kingdom

    X
  • Nick Fox,

    Affiliation: Dementia Research Centre, Department of Neurodegenerative Diseases, UCL Institute of Neurology, London, United Kingdom

    X
  • Martin Rossor,

    Affiliation: Dementia Research Centre, Department of Neurodegenerative Diseases, UCL Institute of Neurology, London, United Kingdom

    X
  • John Collinge,

    Affiliation: MRC Prion Unit, Department of Neurodegenerative Diseases, UCL Institute of Neurology, London, United Kingdom

    X
  • Wolfgang Maier,

    Affiliation: Department of Psychiatry, University of Bonn, Bonn, Germany

    X
  • Frank Jessen,

    Affiliation: Department of Psychiatry, University of Bonn, Bonn, Germany

    X
  • Britta Schürmann,

    Affiliation: Department of Psychiatry, University of Bonn, Bonn, Germany

    X
  • Hendrik van den Bussche,

    Affiliation: Institute of Primary Medical Care, University Medical Center Hamburg-Eppendorf, Germany

    X
  • Isabella Heuser,

    Affiliation: Institute of Primary Medical Care, University Medical Center Hamburg-Eppendorf, Germany

    X
  • Oliver Peters,

    Affiliation: Institute of Primary Medical Care, University Medical Center Hamburg-Eppendorf, Germany

    X
  • Johannes Kornhuber,

    Affiliation: Department of Psychiatry and Psychotherapy, University of Erlangen-Nuremberg, Erlangen, Germany

    X
  • Jens Wiltfang,

    Affiliation: Landschaftsverband Rheinland-Hospital Essen, Department of Psychiatry and Psychotherapy, University Duisburg-Essen, Essen, Germany

    X
  • Martin Dichgans,

    Affiliations: Institute for Stroke and Dementia Research, Klinikum der Universität München, Munich, Germany, Department of Neurology, Klinikum der Universität München, Munich, Germany

    X
  • Lutz Frölich,

    Affiliation: Department of Geriatric Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany

    X
  • Harald Hampel,

    Affiliations: Discipline of Psychiatry, School of Medicine and Trinity College Institute of Neuroscience, Laboratory of Neuroimaging and Biomarker Research, Trinity College, University of Dublin, Dublin, Ireland, Alzheimer Memorial Center and Geriatric Psychiatry Branch, Department of Psychiatry, Ludwig-Maximilian University, Munich, Germany

    X
  • Michael Hüll,

    Affiliation: Centre for Geriatric Medicine and Section of Gerontopsychiatry and Neuropsychology, Medical School, University of Freiburg, Freiburg, Germany

    X
  • Dan Rujescu,

    Affiliation: Alzheimer Memorial Center and Geriatric Psychiatry Branch, Department of Psychiatry, Ludwig-Maximilian University, Munich, Germany

    X
  • Alison M. Goate,

    Affiliation: Departments of Psychiatry, Neurology and Genetics, Washington University School of Medicine, St. Louis, Missouri, United States of America

    X
  • John S. K. Kauwe,

    Affiliation: Department of Biology, Brigham Young University, Provo, Utah, United States of America

    X
  • Carlos Cruchaga,

    Affiliation: Departments of Psychiatry, Neurology and Genetics, Washington University School of Medicine, St. Louis, Missouri, United States of America

    X
  • Petra Nowotny,

    Affiliation: Departments of Psychiatry, Neurology and Genetics, Washington University School of Medicine, St. Louis, Missouri, United States of America

    X
  • John C. Morris,

    Affiliation: Departments of Psychiatry, Neurology and Genetics, Washington University School of Medicine, St. Louis, Missouri, United States of America

    X
  • Kevin Mayo,

    Affiliation: Departments of Psychiatry, Neurology and Genetics, Washington University School of Medicine, St. Louis, Missouri, United States of America

    X
  • Gill Livingston,

    Affiliation: Department of Mental Health Sciences, UCL, London, United Kingdom

    X
  • Nicholas J. Bass,

    Affiliation: Department of Mental Health Sciences, UCL, London, United Kingdom

    X
  • Hugh Gurling,

    Affiliation: Department of Mental Health Sciences, UCL, London, United Kingdom

    X
  • Andrew McQuillin,

    Affiliation: Department of Mental Health Sciences, UCL, London, United Kingdom

    X
  • Rhian Gwilliam,

    Affiliation: The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, United Kingdom

    X
  • Panos Deloukas,

    Affiliation: The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, United Kingdom

    X
  • Ammar Al-Chalabi,

    Affiliation: MRC Centre for Neurodegeneration Research, Department of Clinical Neuroscience, King's College London, Institute of Psychiatry, London, United Kingdom

    X
  • Christopher E. Shaw,

    Affiliation: MRC Centre for Neurodegeneration Research, Department of Clinical Neuroscience, King's College London, Institute of Psychiatry, London, United Kingdom

    X
  • Andrew B. Singleton,

    Affiliation: Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, United States of America

    X
  • Rita Guerreiro,

    Affiliation: Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, United States of America

    X
  • Thomas W. Mühleisen,

    Affiliations: Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany, Institute of Human Genetics, University of Bonn, Bonn, Germany

    X
  • Markus M. Nöthen,

    Affiliations: Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany, Institute of Human Genetics, University of Bonn, Bonn, Germany

    X
  • Susanne Moebus,

    Affiliation: Institute for Medical Informatics, Biometry and Epidemiology, University Hospital of Essen, University Duisburg-Essen, Essen, Germany

    X
  • Karl-Heinz Jöckel,

    Affiliation: Institute for Medical Informatics, Biometry and Epidemiology, University Hospital of Essen, University Duisburg-Essen, Essen, Germany

    X
  • Norman Klopp,

    Affiliation: Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany

    X
  • H.-Erich Wichmann,

    Affiliations: Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany, Institute of Medical Informatics, Biometry and Epidemiology, Ludwig-Maximilians-Universität, Munich, Germany, Klinikum Grosshadern, Munich, Germany

    X
  • Eckhard Rüther,

    Affiliation: Department of Psychiatry, University of Gottingen, Gottingen, Germany

    X
  • Minerva M. Carrasquillo,

    Affiliation: Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, Florida, United States of America

    X
  • V. Shane Pankratz,

    Affiliation: Division of Biomedical Statistics and Informatics, Mayo Clinic and Mayo Foundation, Rochester, Minnesota, United States of America

    X
  • Steven G. Younkin,

    Affiliation: Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, Florida, United States of America

    X
  • John Hardy,

    Affiliation: Department of Molecular Neuroscience and Reta Lilla Weston Laboratories, Institute of Neurology, London, United Kingdom

    X
  • Michael C. O'Donovan,

    Affiliation: Medical Research Council (MRC) Centre for Neuropsychiatric Genetics and Genomics, Department of Psychological Medicine and Neurology, School of Medicine, Cardiff University, Cardiff, United Kingdom

    X
  • Michael J. Owen mail,

    williamsj@cf.ac.uk (JW); owenmj@cf.ac.uk (MJO)

    Affiliation: Medical Research Council (MRC) Centre for Neuropsychiatric Genetics and Genomics, Department of Psychological Medicine and Neurology, School of Medicine, Cardiff University, Cardiff, United Kingdom

    X
  • Julie Williams mail

    williamsj@cf.ac.uk (JW); owenmj@cf.ac.uk (MJO)

    Affiliation: Medical Research Council (MRC) Centre for Neuropsychiatric Genetics and Genomics, Department of Psychological Medicine and Neurology, School of Medicine, Cardiff University, Cardiff, United Kingdom

    X
  • Published: November 15, 2010
  • DOI: 10.1371/journal.pone.0013950

About the Authors

Lesley Jones, Peter A. Holmans, Marian L. Hamshere, Denise Harold, Valentina Moskvina, Dobril Ivanov, Andrew Pocklington, Richard Abraham, Paul Hollingworth, Rebecca Sims, Amy Gerrish, Jaspreet Singh Pahwa, Nicola Jones, Alexandra Stretton, Angharad R. Morgan, Michael C. O'Donovan, Michael J. Owen, Julie Williams
Medical Research Council (MRC) Centre for Neuropsychiatric Genetics and Genomics, Department of Psychological Medicine and Neurology, School of Medicine, Cardiff University, Cardiff, United Kingdom
Simon Lovestone
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, United Kingdom
John Powell, Petroula Proitsi, Michelle K. Lupton
Department of Neuroscience, Institute of Psychiatry, Kings College, London, United Kingdom
Carol Brayne
Institute of Public Health, University of Cambridge, Cambridge, United Kingdom
David C. Rubinsztein
Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom
Michael Gill, Brian Lawlor, Aoibhinn Lynch
Mercer's Institute for Research on Aging, St. James Hospital and Trinity College, Dublin, Ireland
Kevin Morgan, Kristelle S. Brown
Institute of Genetics, Queen's Medical Centre, University of Nottingham, Nottingham, United Kingdom
Peter A. Passmore, David Craig, Bernadette McGuinness, Stephen Todd
Ageing Group, Centre for Public Health, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, United Kingdom
Clive Holmes
Division of Clinical Neurosciences, School of Medicine, University of Southampton, Southampton, United Kingdom
David Mann
Clinical Neuroscience Research Group, Greater Manchester Neurosciences Centre, University of Manchester, Salford, United Kingdom
A. David Smith
Oxford Project to Investigate Memory and Ageing, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom
Seth Love, Patrick G. Kehoe
Dementia Research Group, University of Bristol Institute of Clinical Neurosciences, Frenchay Hospital, Bristol, United Kingdom
Simon Mead, John Collinge
MRC Prion Unit, Department of Neurodegenerative Diseases, UCL Institute of Neurology, London, United Kingdom
Nick Fox, Martin Rossor
Dementia Research Centre, Department of Neurodegenerative Diseases, UCL Institute of Neurology, London, United Kingdom
Wolfgang Maier, Frank Jessen, Britta Schürmann
Department of Psychiatry, University of Bonn, Bonn, Germany
Hendrik van den Bussche, Isabella Heuser, Oliver Peters
Institute of Primary Medical Care, University Medical Center Hamburg-Eppendorf, Germany
Johannes Kornhuber
Department of Psychiatry and Psychotherapy, University of Erlangen-Nuremberg, Erlangen, Germany
Jens Wiltfang
Landschaftsverband Rheinland-Hospital Essen, Department of Psychiatry and Psychotherapy, University Duisburg-Essen, Essen, Germany
Martin Dichgans
Institute for Stroke and Dementia Research, Klinikum der Universität München, Munich, Germany
Martin Dichgans
Department of Neurology, Klinikum der Universität München, Munich, Germany
Lutz Frölich
Department of Geriatric Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
Harald Hampel
Discipline of Psychiatry, School of Medicine and Trinity College Institute of Neuroscience, Laboratory of Neuroimaging and Biomarker Research, Trinity College, University of Dublin, Dublin, Ireland
Harald Hampel, Dan Rujescu
Alzheimer Memorial Center and Geriatric Psychiatry Branch, Department of Psychiatry, Ludwig-Maximilian University, Munich, Germany
Michael Hüll
Centre for Geriatric Medicine and Section of Gerontopsychiatry and Neuropsychology, Medical School, University of Freiburg, Freiburg, Germany
Alison M. Goate, Carlos Cruchaga, Petra Nowotny, John C. Morris, Kevin Mayo
Departments of Psychiatry, Neurology and Genetics, Washington University School of Medicine, St. Louis, Missouri, United States of America
John S. K. Kauwe
Department of Biology, Brigham Young University, Provo, Utah, United States of America
Gill Livingston, Nicholas J. Bass, Hugh Gurling, Andrew McQuillin
Department of Mental Health Sciences, UCL, London, United Kingdom
Rhian Gwilliam, Panos Deloukas
The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, United Kingdom
Ammar Al-Chalabi, Christopher E. Shaw
MRC Centre for Neurodegeneration Research, Department of Clinical Neuroscience, King's College London, Institute of Psychiatry, London, United Kingdom
Andrew B. Singleton, Rita Guerreiro
Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, United States of America
Thomas W. Mühleisen, Markus M. Nöthen
Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany
Thomas W. Mühleisen, Markus M. Nöthen
Institute of Human Genetics, University of Bonn, Bonn, Germany
Susanne Moebus, Karl-Heinz Jöckel
Institute for Medical Informatics, Biometry and Epidemiology, University Hospital of Essen, University Duisburg-Essen, Essen, Germany
Norman Klopp, H.-Erich Wichmann
Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
H.-Erich Wichmann
Institute of Medical Informatics, Biometry and Epidemiology, Ludwig-Maximilians-Universität, Munich, Germany
H.-Erich Wichmann
Klinikum Grosshadern, Munich, Germany
Eckhard Rüther
Department of Psychiatry, University of Gottingen, Gottingen, Germany
Minerva M. Carrasquillo, Steven G. Younkin
Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, Florida, United States of America
V. Shane Pankratz
Division of Biomedical Statistics and Informatics, Mayo Clinic and Mayo Foundation, Rochester, Minnesota, United States of America
John Hardy
Department of Molecular Neuroscience and Reta Lilla Weston Laboratories, Institute of Neurology, London, United Kingdom

Corresponding Authors

Competing Interests

Profs Owen, J Williams and Dr Harold have a patent application in respect of genes identified in the GWAS Harold et al. Nature Genetics 2009;41(10):1088–93; this study provided data for this manuscript and was funded by the MRC and the Wellcome Trust. Dr Passmore has consulted for Pfizer and received compensation. Dr Hull has been funded by Wyeth and consulted for Pfizer, Wyeth and Merz; he has a patent pending for AD diagnostic tests. Dr Lynch has received travel expenses from Pfizer and Novartis. Prof Goate's work has been funded by NIH and AHAF. Prof Fox is a board member of the Alzheimer's Research Forum, has consulted for Abbott Laboratories and has received compensation for consulting for GE Healthcare. He has a patent for QA Box that did not arise from this work which contributes funds to his institution. Dr Morris is funded by NIA. Dr Livingston has received compensation from Lundbeck sa. Ms Stretton holds a CASE PhD studentship jointly funded by MRC and GSK. The remaining authors declare no potential conflict of interest. This does not alter the authors' adherence to all the PloS ONE policies on sharing data and materials.

Author Contributions

Conceived and designed the experiments: LJ PH MO MO JW. Performed the experiments: LJ PH DH RA PH RS AG NJ AS AM RG PD. Analyzed the data: LJ PH MH DH VM DI AP JSP. Contributed reagents/materials/analysis tools: PH SL JP PP MKL CB DCR MG BL AL KM KSB PP DC BM ST CH DM ADS SL PGK SM NCF MR JC WM FJ BS HvdB IH OP JK JW MD LF HH MH DR AMG JSKK CC PN JM KM GL NJB HMG AM AAC CES ABS RG TWM MN SM KHJ NK HEW ER MMC VSP SGY JH MO MO JW. Wrote the paper: LJ PH JH MO MO JW.