Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer's disease

Paul Hollingworth; Denise Harold; Rebecca Sims; Amy Gerrish; Jean-Charles Lambert; Minerva M. Carrasquillo; Richard Abraham; Marian L. Hamshere; Jaspreet Singh Pahwa; Valentina Moskvina; Kimberley Dowzell; Nicola Jones; Alexandra Stretton; Charlene Thomas; Alex Richards; Dobril Ivanov; Caroline Widdowson; Jade Chapman; Simon Lovestone; John Powell; Petroula Proitsi; Michelle K. Lupton; Carol Brayne; David C. Rubinsztein; Michael Gill; Brian Lawlor; Aoibhinn Lynch; Kristelle S. Brown; Peter A. Passmore; David Craig; Bernadette McGuinness; Stephen Todd; Clive Holmes; David Mann; A. David Smith; Helen Beaumont; Donald Warden; Gordon Wilcock; Seth Love; Patrick G. Kehoe; Nigel M. Hooper; Emma R. L. C. Vardy; John Hardy; Simon Mead; Nick C. Fox; Martin Rossor; John Collinge; Wolfgang Maier; Frank Jessen; Eckart Ruether; Britta Schuermann; Reiner Heun; Heike Koelsch; Hendrik van den Bussche; Isabella Heuser; Johannes Kornhuber; Jens Wiltfang; Martin Dichgans; Lutz Froelich; Harald Hampel; John Gallacher; Michael Huell; Dan Rujescu; Ina Giegling; Alison M. Goate; John S. K. Kauwe; Carlos Cruchaga; Petra Nowotny; John C. Morris; Kevin Mayo; Kristel Sleegers; Karolien Bettens; Sebastiaan Engelborghs; Peter P. De Deyn; Christine Van Broeckhoven; Gill Livingston; Nicholas J. Bass; Hugh Gurling; Andrew McQuillin; Rhian Gwilliam; Panagiotis Deloukas; Ammar Al-Chalabi; Christopher E. Shaw; Magda Tsolaki; Andrew B. Singleton; Rita Guerreiro; Thomas W. Muehleisen; Markus M. Noethen; Susanne Moebus; Karl-Heinz Joeckel; Norman Klopp; H-Erich Wichmann; V. Shane Pankratz; Sigrid B. Sando; Jan O. Aasly; Maria Barcikowska; Zbigniew K. Wszolek; Dennis W. Dickson; Neill R. Graff-Radford; Ronald C. Petersen; Cornelia M. van Duijn; Monique M. B. Breteler; M. Arfan Ikram; Anita L. DeStefano; Annette L. Fitzpatrick; Oscar Lopez; Lenore J. Launer; Sudha Seshadri; Claudine Berr; Dominique Campion; Jacques Epelbaum; Jean-Francois Dartigues; Christophe Tzourio; Annick Alperovitch; Mark Lathrop; Thomas M. Feulner; Patricia Friedrich; Caterina Riehle; Michael Krawczak; Stefan Schreiber; Manuel Mayhaus; S. Nicolhaus; Stefan Wagenpfeil; Stacy Steinberg; Hreinn Stefansson; Kari Stefansson; Jon Snaedal; Sigurbjorn Bjornsson; Palmi V. Jonsson; Vincent Chouraki; Benjamin Genier-Boley; Mikko Hiltunen; Hilkka Soininen; Onofre Combarros; Diana Zelenika; Marc Delepine; Maria J. Bullido; Florence Pasquier; Ignacio Mateo; Ana Frank-Garcia; Elisa Porcellini; Olivier Hanon; Eliecer Coto; Victoria Alvarez; Paolo Bosco; Gabriele Siciliano; Michelangelo Mancuso; Francesco Panza; Vincenzo Solfrizzi; Benedetta Nacmias; Sandro Sorbi; Paola Bossu; Paola Piccardi; Beatrice Arosio; Giorgio Annoni; Davide Seripa; Alberto Pilotto; Elio Scarpini; Daniela Galimberti; Alexis Brice; Didier Hannequin; Federico Licastro; Lesley Jones; Peter A. Holmans; Thorlakur Jonsson; Matthias Riemenschneider; Kevin Morgan; Steven G. Younkin; Michael J. Owen; Michael O'Donovan; Philippe Amouyel; Julie Williams; Alzheimer's Dis Neuroimaging

doi:10.1038/ng.803

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Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer's disease

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Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer's disease

Paul Hollingworth, Denise Harold, Rebecca Sims, Amy Gerrish, Jean-Charles Lambert, Minerva M. Carrasquillo, Richard Abraham, Marian L. Hamshere, Jaspreet Singh Pahwa, Valentina Moskvina, …

Nature genetics, Vol.43(5), pp.429-435

01/05/2011

DOI: https://doi.org/10.1038/ng.803

PMCID: PMC3084173

PMID: 21460840

Abstract

Genetics & Heredity

Life Sciences & Biomedicine

Science & Technology

We sought to identify new susceptibility loci for Alzheimer's disease through a staged association study (GERAD+) and by testing suggestive loci reported by the Alzheimer's Disease Genetic Consortium (ADGC) in a companion paper. We undertook a combined analysis of four genome-wide association datasets (stage 1) and identified ten newly associated variants with P <= 1 x 10(-5). We tested these variants for association in an independent sample (stage 2). Three SNPs at two loci replicated and showed evidence for association in a further sample (stage 3). Meta-analyses of all data provided compelling evidence that ABCA7 (rs3764650, meta P = 4.5 x 10(-17); including ADGC data, meta P = 5.0 x 10(-21)) and the MS4A gene cluster (rs610932, meta P = 1.8 x 10(-14); including ADGC data, meta P = 1.2 x 10(-16)) are new Alzheimer's disease susceptibility loci. We also found independent evidence for association for three loci reported by the ADGC, which, when combined, showed genome-wide significance: CD2AP (GERAD+, P = 8.0 x 10(-4); including ADGC data, meta P = 8.6 x 10(-9)), CD33 (GERAD+, P = 2.2 x 10(-4); including ADGC data, meta P = 1.6 x 10(-9)) and EPHA1 (GERAD+, P = 3.4 x 10(-4); including ADGC data, meta P = 6.0 x 10(-10)).

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Title: Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer's disease
Creators - without role: Paul Hollingworth - Cardiff University
Denise Harold - Cardiff University
Rebecca Sims - Cardiff University
Amy Gerrish - Cardiff University
Jean-Charles Lambert - Inserm
Minerva M. Carrasquillo - College Station Medical Center
Richard Abraham - Cardiff University
Marian L. Hamshere - Cardiff University
Jaspreet Singh Pahwa - Cardiff University
Valentina Moskvina - Cardiff University
Kimberley Dowzell - Cardiff University
Nicola Jones - Cardiff University
Alexandra Stretton - Cardiff University
Charlene Thomas - Cardiff University
Alex Richards - Cardiff University
Dobril Ivanov - Cardiff University
Caroline Widdowson - Cardiff University
Jade Chapman - Cardiff University
Simon Lovestone - Kings Coll London, Natl Inst Hlth Res, Biomed Res Ctr Mental Hlth, S London & Maudsley Natl Hlth Serv Fdn Trust, London WC2R 2LS, England
John Powell - Kings Coll London, Inst Psychiat, Dept Neurosci, London WC2R 2LS, England
Petroula Proitsi - Kings Coll London, Inst Psychiat, Dept Neurosci, London WC2R 2LS, England
Michelle K. Lupton - Kings Coll London, Inst Psychiat, Dept Neurosci, London WC2R 2LS, England
Carol Brayne - University of Cambridge
David C. Rubinsztein - University of Cambridge
Michael Gill - St James Hosp, Mercers Inst Res Aging, Dublin 8, Ireland
Brian Lawlor - St James Hosp, Mercers Inst Res Aging, Dublin 8, Ireland
Aoibhinn Lynch - St James Hosp, Mercers Inst Res Aging, Dublin 8, Ireland
Kristelle S. Brown - University of Nottingham
Peter A. Passmore - Queens University
David Craig - Queens University
Bernadette McGuinness - Queens University
Stephen Todd - Queens University
Clive Holmes - University of Southampton
David Mann - University of Manchester
A. David Smith - University of Oxford
Helen Beaumont - University of Oxford
Donald Warden - University of Oxford
Gordon Wilcock - University of Oxford
Seth Love - University of Bristol
Patrick G. Kehoe - University of Bristol
Nigel M. Hooper - University of Leeds
Emma R. L. C. Vardy - University of Manchester
John Hardy - Inst Neurol, Dept Mol Neurosci, London WC1N 3BG, England
Simon Mead - UCL, Inst Neurol, Dept Neurodegenerat Dis, London, England
Nick C. Fox - UCL, Inst Neurol, Dept Neurodegenerat Dis, London, England
Martin Rossor - UCL, Inst Neurol, Dept Neurodegenerat Dis, London, England
John Collinge - UCL, Inst Neurol, Dept Neurodegenerat Dis, London, England
Wolfgang Maier - University of Bonn
Frank Jessen - University of Bonn
Eckart Ruether - German Ctr Neurodegenerat Dis, Bonn, Germany
Britta Schuermann - University of Bonn
Reiner Heun - University of Bonn
Heike Koelsch - University of Bonn
Hendrik van den Bussche - Univ Med Ctr Hamburg Eppendorf, Inst Primary Med Care, Hamburg, Germany
Isabella Heuser - Charité - Universitätsmedizin Berlin
Johannes Kornhuber - Univ Erlangen Nurnberg, Dept Psychiat & Psychotherapy, Nurnberg, Germany
Jens Wiltfang - University of Duisburg-Essen
Martin Dichgans - Klinikum Univ Munchen, Dept Neurol, Munich, Germany
Lutz Froelich - Heidelberg Univ, Dept Geriatr Psychiat, Cent Inst Mental Hlth, Med Fac Mannheim, D-6800 Mannheim, Germany
Harald Hampel - Goethe University Frankfurt
John Gallacher - Cardiff University
Michael Huell - University of Freiburg
Dan Rujescu - University of Freiburg
Ina Giegling - Cardiff University
Alison M. Goate - Supreme Council Of Health
John S. K. Kauwe - Brigham Young University
Carlos Cruchaga - Supreme Council Of Health
Petra Nowotny - Supreme Council Of Health
John C. Morris - Supreme Council Of Health
Kevin Mayo - Supreme Council Of Health
Kristel Sleegers - University of Antwerp
Karolien Bettens - University of Antwerp
Sebastiaan Engelborghs - University of Antwerp
Peter P. De Deyn - University of Antwerp
Christine Van Broeckhoven - University of Antwerp
Gill Livingston - UCL, Dept Mental Hlth Sci, London, England
Nicholas J. Bass - UCL, Dept Mental Hlth Sci, London, England
Hugh Gurling - UCL, Dept Mental Hlth Sci, London, England
Andrew McQuillin - UCL, Dept Mental Hlth Sci, London, England
Rhian Gwilliam - Wellcome Sanger Institute
Panagiotis Deloukas - Wellcome Sanger Institute
Ammar Al-Chalabi - Massachusetts Rehabilitation Commission
Christopher E. Shaw - Massachusetts Rehabilitation Commission
Magda Tsolaki - Aristotle University of Thessaloniki
Andrew B. Singleton - NIA, Lab Neurogenet, NIH, Bethesda, MD 20892 USA
Rita Guerreiro - NIA, Lab Neurogenet, NIH, Bethesda, MD 20892 USA
Thomas W. Muehleisen - University of Bonn
Markus M. Noethen - University of Bonn
Susanne Moebus - University of Duisburg-Essen
Karl-Heinz Joeckel - University of Duisburg-Essen
Norman Klopp - Helmholtz Zentrum München
H-Erich Wichmann - Helmholtz Zentrum München
V. Shane Pankratz - Univ Munich, Div Biomed Stat, Munich, Germany
Sigrid B. Sando - St Olavs Hosp, Dept Neurol, Trondheim, Norway
Jan O. Aasly - St Olavs Hosp, Dept Neurol, Trondheim, Norway
Maria Barcikowska - College Station Medical Center
Zbigniew K. Wszolek
Dennis W. Dickson - College Station Medical Center
Neill R. Graff-Radford - College Station Medical Center
Ronald C. Petersen - College Station Medical Center
Cornelia M. van Duijn - College Station Medical Center
Monique M. B. Breteler - College Station Medical Center
M. Arfan Ikram - College Station Medical Center
Anita L. DeStefano - Boston University
Annette L. Fitzpatrick - University of Washington
Oscar Lopez - College Station Medical Center
Lenore J. Launer - NIA, Neuroepidemiol Sect, Lab Epidemiol Demog & Biometry LJL, Washington, DC USA
Sudha Seshadri - NHLBI, Framingham, MA USA
Claudine Berr - Inserm
Dominique Campion - Inserm
Jacques Epelbaum - Université Paris Cité
Jean-Francois Dartigues - Inserm
Christophe Tzourio - Inserm
Annick Alperovitch - Inserm
Mark Lathrop - Evry
Thomas M. Feulner - Univ Saarland, Dept Psychiat & Psychotherapy, Univ Klinikum Saarlandes, Saarbrucken, Germany
Patricia Friedrich - Univ Saarland, Dept Psychiat & Psychotherapy, Univ Klinikum Saarlandes, Saarbrucken, Germany
Caterina Riehle - Univ Saarland, Dept Psychiat & Psychotherapy, Univ Klinikum Saarlandes, Saarbrucken, Germany
Michael Krawczak - College Station Medical Center
Stefan Schreiber - College Station Medical Center
Manuel Mayhaus - Univ Saarland, Dept Psychiat & Psychotherapy, Univ Klinikum Saarlandes, Saarbrucken, Germany
S. Nicolhaus - Univ Kiel, Inst Clin Mol Biol, Kiel, Germany
Stefan Wagenpfeil - College Station Medical Center
Stacy Steinberg - DeCODE Genet, Reykjavik, Iceland
Hreinn Stefansson - DeCODE Genet, Reykjavik, Iceland
Kari Stefansson - DeCODE Genet, Reykjavik, Iceland
Jon Snaedal - University of Iceland
Sigurbjorn Bjornsson - University of Iceland
Palmi V. Jonsson - University of Iceland
Vincent Chouraki - Inserm
Benjamin Genier-Boley - Inserm
Mikko Hiltunen - University of Eastern Finland
Hilkka Soininen - University of Eastern Finland
Onofre Combarros - Universidad de Cantabria
Diana Zelenika - Evry
Marc Delepine - Evry
Maria J. Bullido - Universidad de Cantabria
Florence Pasquier - Univ Lille Nord France, F-59000 Lille, France
Ignacio Mateo - Universidad de Cantabria
Ana Frank-Garcia - Universidad de Cantabria
Elisa Porcellini - University of Bologna
Olivier Hanon - Université Paris Cité
Eliecer Coto - Hosp Univ Cent Asturias, Genet Mol Unit, Oviedo, Spain
Victoria Alvarez - Hosp Univ Cent Asturias, Genet Mol Unit, Oviedo, Spain
Paolo Bosco - Ist Di Ricovero & Cura Carattere Sci Oasi Maria S, Troina, Italy
Gabriele Siciliano - University of Pisa
Michelangelo Mancuso - University of Pisa
Francesco Panza - University of Bari Aldo Moro
Vincenzo Solfrizzi - University of Bari Aldo Moro
Benedetta Nacmias - University of Florence
Sandro Sorbi - University of Florence
Paola Bossu - IRCCS Santa Lucia Fdn, Dept Clin & Behav Neurol, Rome, Italy
Paola Piccardi - University of Cagliari
Beatrice Arosio - University of Milan
Giorgio Annoni - University of Milano-Bicocca
Davide Seripa - CASA
Alberto Pilotto - CASA
Elio Scarpini - University of Milan
Daniela Galimberti - University of Milan
Alexis Brice - Inserm
Didier Hannequin - Inserm
Federico Licastro - University of Bologna
Lesley Jones - Cardiff University
Peter A. Holmans - Cardiff University
Thorlakur Jonsson - DeCODE Genet, Reykjavik, Iceland
Matthias Riemenschneider - Univ Saarland, Dept Psychiat & Psychotherapy, Univ Klinikum Saarlandes, Saarbrucken, Germany
Kevin Morgan - University of Nottingham
Steven G. Younkin - College Station Medical Center
Michael J. Owen - Cardiff University
Michael O'Donovan - Cardiff University
Philippe Amouyel - Inserm
Julie Williams - Cardiff University
Alzheimer's Dis Neuroimaging
Publication Details: Nature genetics, Vol.43(5), pp.429-435
Publisher: Springer Nature
Number of pages: 8
Grant note: Welsh Assembly Government National Institute of Biomedical Imaging Bioengineering; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Biomedical Imaging & Bioengineering (NIBIB) Ministry for Health, Welfare and Sports Dunhill Medical Trust Italian Ministry of Research; Ministry of Education, Universities and Research (MIUR) Netherlands organization for scientific research; Netherlands Organization for Scientific Research (NWO) US National Institutes of Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA Northern Ireland RD Office Innogenetics Lundbeck; Lundbeck Corporation Netherlands Organization for the Health Research and Development; Netherlands Organization for Health Research and Development G0701075; MC_U123160651; G0801306; G0802189; G0601846; MC_G1000734; G0900688; G0902227; G9810900; G0300429 / MRC; UK Research & Innovation (UKRI); Medical Research Council UK (MRC) Agence Francaise de Securite Sanitaire des Produits de Sante Institut Pasteur de Lille Eli Lilly Abbott; Abbott Laboratories Alfried Krupp von Bohlen und Halbach-Stiftung Pfizer Mayo AD Research Center Nationale Maladie des Travailleurs Salaries, Direction Generale de la Sant French Ministry of Research/Institute national de la sante et de la recherche medicale; Institut National de la Sante et de la Recherche Medicale (Inserm); Ministry of Research, France German National Genome Research Network Medpace German Ministry for Education and Research; Federal Ministry of Education & Research (BMBF) Althingi National Heart Lung and Blood Institute; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Heart Lung & Blood Institute (NHLBI) Alzheimer's Association NIHR Biomedical Research Centre, Oxford; National Institutes of Health Research (NIHR) European Commission; European Commission Joint Research Centre Fundacion Ramon Areces Ministerio de Educacion y Ciencia the Ministerio de Sanidad y Consumo Robert and Clarice Smith Postdoctoral Fellowship and AD Research Program Netherlands Organisation of Scientific Research; Netherlands Organization for Scientific Research (NWO) Methusalem Excellence grant Barnes Jewish Foundation Eisai; Eisai Co Ltd University College London (UCL) Hospital/UCL Biomedical Centre US Food and Drug Administration; United States Department of Health & Human Services; US Food & Drug Administration (FDA) National Institute of Diabetes and Digestive and Kidney Diseases; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK) Alzheimer's Drug Discovery Foundation Carl Edward and Susan Bass Bolch Gift Mercer's Institute for Research on Ageing Charles and Joanne Knight Alzheimer's Research Initiative Nordic Centre of Excellence in Neurodegeneration Wellcome Trust Bristol-Myers Squibb Health Research Council of the Academy of Finland; Research Council of Finland Alzheimer's Research UK; Alzheimer's Research UK (ARUK) Centre National de Genotypage Dana Foundation Municipality of Rotterdam Foundation for the National Institutes of Health Northern California Institute for Research and Education Institut de la Longevite Medical Research Council (UK); UK Research & Innovation (UKRI); Medical Research Council UK (MRC) Alzheimer's Society GE Johnson and Johnson; Johnson & Johnson; Johnson & Johnson USA National Institute of Neurological Disorders and Stroke; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Neurological Disorders & Stroke (NINDS) German Federal Ministry of Education and Research Competence Network Dementia and Competence Network Degenerative Dementia; Federal Ministry of Education & Research (BMBF) Elan Federal Science Policy Office; Belgian Federal Science Policy Office Italian Ministry of Health; Ministry of Health, Italy Hoffman-La Roche Hjartavernd Royal College of Physicians University of Antwerp Fondation de France Carimonte Foundation National Institute on Deafness and Other Communication Disorders; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute on Deafness & Other Communication Disorders (NIDCD) ART-PPG2011A-14; ART-SB2010A-1; ART-NCG2008A-1; ART-BIG2009-1; ART-RF2007-3; ART-PG2010-1 / Alzheimers Research UK; Alzheimer's Research UK (ARUK) AstraZeneca Synarc Bristol Research into Alzheimer's and Care of the Eldery National Institute of Ageing Department of Health and Human Services Fondation pour la Recherche Medicale Caisse Merck; Merck & Company Novartis Research Institute for Diseases in the Elderly G0601846; MC_U123160651; G0802189; G0801306; G9810900; G0701075; MC_G1000734; G0902227; G0900688; G0801418B; G0300429 / Medical Research Council; UK Research & Innovation (UKRI); Medical Research Council UK (MRC) Ministry of Education, Culture and Science; Ministry of Education, Culture, Sports, Science and Technology, Japan (MEXT) Ulster Garden Villages Wyeth Palumbo Professorship in AD Research Netherlands Genomics Initiative Bayer Schering Pharma; Bayer AG Schering-Plough; Merck & Company; Schering Plough Corporation Fund for Scientific Research-Flanders; FWO Robert Dawson Evans Endowment Aquitaine and Bourgogne Regional Councils; Region Bourgogne-Franche-Comte Foundation for Alzheimer Research GlaxoSmithKline Health Foundation Fondazione Monzino Erasmus Medical Center Genentech; Roche Holding
Identifiers: 9935901408331
Academic Unit: King Abdulaziz University
Language: English
Resource Type: Journal article