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

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; 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; Clive Holmes; David Mann; A. David Smith; Seth Love; Patrick G. Kehoe; Simon Mead; Nick Fox; Martin Rossor; John Collinge; Wolfgang Maier; Frank Jessen; Britta Schuermann; Hendrik van den Bussche; Isabella Heuser; Oliver Peters; Johannes Kornhuber; Jens Wiltfang; Martin Dichgans; Lutz Froelich; Harald Hampel; Michael Huell; 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; Panos Deloukas; Ammar Al-Chalabi; Christopher E. Shaw; Andrew B. Singleton; Rita Guerreiro; Thomas W. Muehleisen; Markus M. Noethen; Susanne Moebus; Karl-Heinz Joeckel; Norman Klopp; H. -Erich Wichmann; Eckhard Ruether; Minerva M. Carrasquillo; V. Shane Pankratz; Steven G. Younkin; John Hardy; Michael C. O'Donovan; Michael J. Owen; Julie Williams

doi:10.1371/journal.pone.0013950

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

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

Lesley Jones, Peter A. Holmans, Marian L. Hamshere, Denise Harold, Valentina Moskvina, Dobril Ivanov, Andrew Pocklington, Richard Abraham, Paul Hollingworth, Rebecca Sims, …

PloS one, Vol.5(11), pp.e13950-e13950

15/11/2010

DOI: https://doi.org/10.1371/journal.pone.0013950

PMCID: PMC2981526

PMID: 21085570

Abstract

Multidisciplinary Sciences

Science & Technology

Science & Technology - Other Topics

Background: Late 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.

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Title: Genetic Evidence Implicates the Immune System and Cholesterol Metabolism in the Aetiology of Alzheimer's Disease
Creators - without role: Lesley Jones - Cardiff University
Peter A. Holmans - Cardiff University
Marian L. Hamshere - Cardiff University
Denise Harold - Cardiff University
Valentina Moskvina - Cardiff University
Dobril Ivanov - Cardiff University
Andrew Pocklington - Cardiff University
Richard Abraham - Cardiff University
Paul Hollingworth - Cardiff University
Rebecca Sims - Cardiff University
Amy Gerrish - Cardiff University
Jaspreet Singh Pahwa - Cardiff University
Nicola Jones - Cardiff University
Alexandra Stretton - Cardiff University
Angharad R. Morgan - Cardiff University
Simon Lovestone - South London and Maudsley NHS Foundation Trust
John Powell - King's College London
Petroula Proitsi - King's College London
Michelle K. Lupton - King's College London
Carol Brayne - University of Cambridge
David C. Rubinsztein - University of Cambridge
Michael Gill - Trinity College Dublin
Brian Lawlor - Trinity College Dublin
Aoibhinn Lynch - Trinity College Dublin
Kevin Morgan - Queen's Medical Centre
Kristelle S. Brown - University of Nottingham
Peter A. Passmore - Queen's University Belfast
David Craig - Queen's University Belfast
Bernadette McGuinness - Queen's University Belfast
Stephen Todd - Queen's University Belfast
Clive Holmes - University of Southampton
David Mann - University of Manchester
A. David Smith - John Radcliffe Hospital
Seth Love - Frenchay Hospital
Patrick G. Kehoe - Frenchay Hospital
Simon Mead - MRC Prion Unit
Nick Fox - UK Dementia Research Institute
Martin Rossor - UK Dementia Research Institute
John Collinge - MRC Prion Unit
Wolfgang Maier - University of Bonn
Frank Jessen - University of Bonn
Britta Schuermann - University of Bonn
Hendrik van den Bussche - University Medical Center Hamburg-Eppendorf
Isabella Heuser - University Medical Center Hamburg-Eppendorf
Oliver Peters - University Medical Center Hamburg-Eppendorf
Johannes Kornhuber - Friedrich-Alexander-Universität Erlangen-Nürnberg
Jens Wiltfang - University of Duisburg-Essen
Martin Dichgans - LMU Klinikum
Lutz Froelich - Heidelberg Univ, Med Fac Mannheim, Cent Inst Mental Hlth, Dept Geriatr Psychiat, D-6800 Mannheim, Germany
Harald Hampel - Trinity College Dublin
Michael Huell - University of Freiburg
Dan Rujescu - Ludwig-Maximilians-Universität München
Alison M. Goate - Washington University in St. Louis
John S. K. Kauwe - Brigham Young University
Carlos Cruchaga - Washington University in St. Louis
Petra Nowotny - Washington University in St. Louis
John C. Morris - Washington University in St. Louis
Kevin Mayo - Washington University in St. Louis
Gill Livingston - Mental Health Research UK
Nicholas J. Bass - Mental Health Research UK
Hugh Gurling - Mental Health Research UK
Andrew McQuillin - Mental Health Research UK
Rhian Gwilliam - Wellcome Sanger Institute
Panos Deloukas - Wellcome Sanger Institute
Ammar Al-Chalabi - King's College London
Christopher E. Shaw - King's College London
Andrew B. Singleton - National Institute on Aging
Rita Guerreiro - National Institute on Aging
Thomas W. Muehleisen - University of Bonn
Markus M. Noethen - University of Bonn
Susanne Moebus - University of Duisburg-Essen
Karl-Heinz Joeckel
Norman Klopp - Helmholtz Zentrum München
H. -Erich Wichmann - Zimmer Biomet
Eckhard Ruether - University of Göttingen
Minerva M. Carrasquillo - Jacksonville College
V. Shane Pankratz - Mayo Clinic
Steven G. Younkin - Jacksonville College
John Hardy - Inst Neurol, Dept Mol Neurosci, London WC1N 3BG, England
Michael C. O'Donovan - Cardiff University
Michael J. Owen - Cardiff University
Julie Williams - Cardiff University
Publication Details: PloS one, Vol.5(11), pp.e13950-e13950
Publisher: Public Library Science
Number of pages: 11
Grant note: Wellcome Trust Welsh Assembly Government NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA Alzheimer's Society Oxford Project to Investigate Memory and Ageing (OPTIMA) group Robert and Clarice Smith and Abigail Van Buren AD Research Program Northern Ireland Research and Development Office Royal College of Physicians-Dunhill Medical Trust; Dunhill Medical Trust ZIAAG000950; Z01AG000950 / NATIONAL INSTITUTE ON AGING; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute on Aging (NIA) Helmholtz Zentrum Munchen; Helmholtz Association MRC; UK Research & Innovation (UKRI); Medical Research Council UK (MRC) P6/43 / Belgian Federal Science Policy Office US National Institutes of Health (NIH); United States Department of Health & Human Services; National Institutes of Health (NIH) - USA BMBF; Federal Ministry of Education & Research (BMBF) Trinity College group University of Antwerp ART-BIG2009-1; ART-RF2007-3; ART-PG2010-1; ART-NCG2008A-1 / Alzheimers Research UK; Alzheimer's Research UK (ARUK) Bristol Research into Alzheimer's and Care of the Elderly Motor Neurone Disease Association German National Genome Research Network Z01 AG000950-06 / NIA, NIH, Department of Health and Human Services; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute on Aging (NIA) German Research Center for Environmental Health G0900688; G0300429; G0701075; MC_U123192748; MC_U123160651; G0601846; G0600974; G0801418 / MRC; UK Research & Innovation (UKRI); Medical Research Council UK (MRC) Ulster Garden Villages Munich Center of Health Sciences Fund for Scientific Research-Flanders; FWO G0801418B; MC_U123192748; MC_U123160651; G0900688; G0601846; G0300429; G0600974; G0801418; G0701075 / Medical Research Council; UK Research & Innovation (UKRI); Medical Research Council UK (MRC); European Commission Barnes Jewish Foundation Medical Research Council (MRC, UK); UK Research & Innovation (UKRI); Medical Research Council UK (MRC) National Institute on Aging (NIA); United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute on Aging (NIA) Charles and Joanne Knight Alzheimer's Research Initiative Alzheimer's Research Trust (ART) UCL Hospital/UCL Biomedical Centre
Identifiers: 9938447808331
Academic Unit: King Abdulaziz University
Language: English
Resource Type: Journal article