Genetic evidence implicates the immune system and cholesterol metabolism in the aetiology of Alzheimer's disease

Jones, Lesley ORCID: https://orcid.org/0000-0002-3007-4612, Holmans, Peter Alan ORCID: https://orcid.org/0000-0003-0870-9412, Hamshere, Marian Lindsay ORCID: https://orcid.org/0000-0002-8990-0958, Harold, Denise ORCID: https://orcid.org/0000-0001-5195-0143, Moskvina, Valentina ORCID: https://orcid.org/0000-0003-1784-5483, Ivanov, Dobril ORCID: https://orcid.org/0000-0001-6271-6301, Pocklington, Andrew ORCID: https://orcid.org/0000-0002-2137-0452, Abraham, Richard Alun, Hollingworth, Paul, Sims, Rebecca ORCID: https://orcid.org/0000-0002-3885-1199, Gerrish, Amy, Pahwa, Jaspreet Singh, Jones, Nicola, Stretton, Alexandra, Morgan, Angharad Rhys, Lovestone, Simon, Powell, John, Proitsi, Petroula, Lupton, Michelle K., Brayne, Carol, Rubinsztein, David C., Gill, Michael, Lawlor, Brian, Lynch, Aoibhinn, Morgan, Kevin, Brown, Kristelle S., Passmore, Peter A., Craig, David, McGuinness, Bernadette, Todd, Stephen, Holmes, Clive, Mann, David, Smith, A. David, Love, Seth, Kehoe, Patrick G., Mead, Simon, Fox, Nick, Rossor, Martin, Collinge, John, Maier, Wolfgang, Jessen, Frank, Schürmann, Britta, Heun, Reinhard, Kölsch, Heike, van den Bussche, Hendrik, Heuser, Isabella, Peters, Oliver, Kornhuber, Johannes, Wiltfang, Jens, Dichgans, Martin, Frölich, Lutz, Hampel, Harald, Hüll, Michael, Rujescu, Dan, Goate, Alison M., Kauwe, John S. K., Cruchaga, Carlos, Nowotny, Petra, Mayo, Kevin, Morris, John C., Livingston, Gill, Bass, Nicholas J., Gurling, Hugh, McQuillin, Andrew, Gwilliam, Rhian, Deloukas, Panos, Al-Chalabi, Ammar, Shaw, Christopher E., Singleton, Andrew B., Guerreiro, Rita, Mühleisen, Thomas W., Nöthen, Markus M., Moebus, Susanne, Jöckel, Karl-Heinz, Klopp, Norman, Wichmann, H.-Erich, Rüther, Eckhard, Carrasquillo, Minerva M., Pankratz, V. Shane, Younkin, Steven G., Hardy, John, O'Donovan, Michael Conlon ORCID: https://orcid.org/0000-0001-7073-2379, Williams, Julie ORCID: https://orcid.org/0000-0002-4069-0259 and Owen, Michael John ORCID: https://orcid.org/0000-0003-4798-0862 2010. Genetic evidence implicates the immune system and cholesterol metabolism in the aetiology of Alzheimer's disease. PLoS ONE 5 (11) , e13950. 10.1371/journal.pone.0013950

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Abstract

Background 1Late Onset Alzheimer's disease (LOAD) is the leading cause of dementia. Recent large genome-wide association studies (GWAS) identified the first strongly supported LOAD susceptibility genes since the discovery of the involvement of APOE in the early 1990s. We have now exploited these GWAS datasets to uncover key LOAD pathophysiological processes. Methodology We applied a recently developed tool for mining GWAS data for biologically meaningful information to a LOAD GWAS dataset. The principal findings were then tested in an independent GWAS dataset. Principal Findings We found a significant overrepresentation of association signals in pathways related to cholesterol metabolism and the immune response in both of the two largest genome-wide association studies for LOAD. Significance Processes related to cholesterol metabolism and the innate immune response have previously been implicated by pathological and epidemiological studies of Alzheimer's disease, but it has been unclear whether those findings reflected primary aetiological events or consequences of the disease process. Our independent evidence from two large studies now demonstrates that these processes are aetiologically relevant, and suggests that they may be suitable targets for novel and existing therapeutic approaches.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG) Medicine Systems Immunity Research Institute (SIURI) Neuroscience and Mental Health Research Institute (NMHRI)
Subjects:	R Medicine > R Medicine (General) R Medicine > RC Internal medicine > RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry
Additional Information:	Reinhard Heun and Heike Kölsch added to byline in correction published on 11/02/2011, https://doi.org/10.1371/annotation/a0bb886d-d345-4a20-a82e-adce9b047798
Publisher:	Public Library of Science
ISSN:	1932-6203
Date of First Compliant Deposit:	30 March 2016
Last Modified:	05 Jan 2024 04:42
URI:	https://orca.cardiff.ac.uk/id/eprint/37552

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