Year: 2012
Type: article
Study design: Observational Study
Abstract: Rare mutations in AβPP, PSEN1, and PSEN2 cause uncommon early onset forms of Alzheimer's disease (AD), and common variants in MAPT are associated with risk of other neurodegenerative disorders. We sought to establish whether common genetic variation in these genes confer risk to the common form of AD which occurs later in life (>65 years). We therefore tested single-nucleotide polymorphisms at these loci for association with late-onset AD (LOAD) in a large case-control sample consisting of 3,940 cases and 13,373 controls. Single-marker analysis did not identify any variants that reached genome-wide significance, a result which is supported by other recent genome-wide association studies. However, we did observe a significant association at the MAPT locus using a gene-wide approach (p = 0.009). We also observed suggestive association between AD and the marker rs9468, which defines the H1 haplotype, an extended haplotype that spans the MAPT gene and has previously been implicated in other neurodegenerative disorders including Parkinson's disease, progressive supranuclear palsy, and corticobasal degeneration. In summary common variants at AβPP, PSEN1, and PSEN2 and MAPT are unlikely to make strong contributions to susceptibility for LOAD. However, the gene-wide effect observed at MAPT indicates a possible contribution to disease risk which requires further study.
Source: Journal of Alzheimer s Disease
Authors: Amy Gerrish, Giancarlo Russo, Alexander Richards, Valentina Moskvina, Dobril Ivanov, Denise Harold, Rebecca Sims, Richard Abraham, Paul Hollingworth, Jade Chapman, Marian Hamshere, Jaspreet Singh Pahwa, Kimberley Dowzell, Amy Williams, Nicola Jones, Charlene Thomas, Alexandra Stretton, Angharad R. Morgan, Simon Lovestone, John Powell, Petroula Proitsi, Michelle K. Lupton, Carol Brayne, David C. Rubinsztein, Michael Gill, Brian Lawlor, Aoibhinn Lynch, Kevin Morgan, Kristelle S. Brown, Peter A. Passmore, David Craig, Bernadette McGuinness, Stephen Todd, Janet A. Johnston, Clive Holmes, David Mann, A. David Smith, Seth Love, Patrick G. Kehoe, John Hardy, Simon Mead, Nick Fox, Martin Rossor, John Collinge, Wolfgang Maier, Frank Jessen, Heike Kölsch, Reinhard Heun, Britta Schürmann, Hendrik van den Bussche, Isabella Heuser, Johannes Kornhuber, Jens Wiltfang, Martin Dichgans, Lutz Frölich, Harald Hampel, Michael Hüll, Dan Rujescu, Alison M. Goate, John S. K Kauwe, Carlos Cruchaga, Petra Nowotny, John C. Morris, Kevin Mayo, Gill Livingston, Nicholas J. Bass, Hugh Gurling, Andrew McQuillin, Rhian Gwilliam, Panagiotis Deloukas, Gail Davies, Sarah E. Harris, John M. Starr, Ian J. Deary, Ammar Al-Chalabi, Christopher E. Shaw, Magda Tsolaki, Andrew B. Singleton, Rita Guerreiro, Thomas W. Mühleisen, Markus M. Nöthen, Susanne Moebus, Karl-Heinz Jöckel, Norman Klopp, H-Erich Wichmann, Minerva M Carrasquillo, V Shane Pankratz, Steven G. Younkin, Lesley Jones, Peter A Holmans, Michael C. O'Donovan, Michael J. Owen, Julie Williams
Institutions: Cardiff University, King's College London, University of Cambridge, Trinity College Dublin, St. James's Hospital, University of Nottingham, Queen's Medical Centre, Queen's University Belfast, University of Southampton, University of Manchester, John Radcliffe Hospital, University of Oxford, Frenchay Hospital, University of Bristol, UCL Queen Square Institute of Neurology, MRC Prion Unit, University College London, University of Bonn, Royal Derby Hospital, University Medical Center Hamburg-Eppendorf, Charité – Universitätsmedizin Berlin, Friedrich-Alexander-Universität Erlangen-Nürnberg, University of Duisburg-Essen, Institut für Schlaganfall- und Demenzforschung, Ludwig-Maximilians-Universität München, Heidelberg University, Central Institute of Mental Health, Medizinische Fakultät Mannheim, Goethe University Frankfurt, Washington University in St. Louis, Brigham Young University, Wellcome Sanger Institute, University of Edinburgh, Alzheimer Scotland, Aristotle University of Thessaloniki, National Institutes of Health, National Institute on Aging, Life & Brain (Germany), Essen University Hospital, Helmholtz Munich, München Klinik, Institut für Medizinische Informationsverarbeitung, Biometrie und Epidemiologie, Mayo Clinic, Mayo Clinic in Florida, Medical Research Council
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: hybrid
Funders: Juvenile Diabetes Research Foundation International, American Federation for Aging Research, Wellcome Trust, Scottish Government, Alzheimer's Society, National Institute for Health and Care Research, Royal Society, Parkinson's UK, Motor Neurone Disease Association, Age UK, University College London, University of Edinburgh, Cardiff University, Bundesministerium für Bildung und Forschung, Alfried Krupp von Bohlen und Halbach-Stiftung, H. Lundbeck A/S, Centre for Cognitive Ageing and Cognitive Epidemiology, Heinz Nixdorf Stiftung, National Institutes of Health, Directorate for Biological Sciences, Medical Research Council, Engineering and Physical Sciences Research Council, Biotechnology and Biological Sciences Research Council, Economic and Social Research Council, Helmholtz Zentrum München, National Institute on Aging, National Institute of Mental Health, National Institute of Allergy and Infectious Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Child Health and Human Development
Awards: G1093300281, G3327757157, G4746977625, G4856618060, NIHR Senior Investigator Award, Alzheimer's Disease Research Center, A genome-wide association study of non-pathological cognitive ageing, Healthy Aging and Senile Dementia, G7572990571, G7584390538, NIHR Senior Investigator Award, Autophagy in health and disease.
OpenAlex ID: W1916743150