Letter abstract
Nature Genetics 41, 1094 - 1099 (2009)
Published online: 6 September 2009 | doi:10.1038/ng.439
Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer's disease
Jean-Charles Lambert1,2,3, Simon Heath4, Gael Even1,2, Dominique Campion5, Kristel Sleegers6,7, Mikko Hiltunen8, Onofre Combarros9, Diana Zelenika4, Maria J Bullido10, Béatrice Tavernier11, Luc Letenneur12, Karolien Bettens6,7, Claudine Berr13, Florence Pasquier3,14, Nathalie Fiévet1,2, Pascale Barberger-Gateau12, Sebastiaan Engelborghs7,15, Peter De Deyn7,15, Ignacio Mateo9, Ana Franck16, Seppo Helisalmi8, Elisa Porcellini17, Olivier Hanon18, the European Alzheimer's Disease Initiative Investigators19, Marian M de Pancorbo20, Corinne Lendon21, Carole Dufouil22,23, Céline Jaillard24, Thierry Leveillard24, Victoria Alvarez25, Paolo Bosco26, Michelangelo Mancuso27, Francesco Panza28, Benedetta Nacmias29, Paola Bossù30, Paola Piccardi31, Giorgio Annoni32, Davide Seripa33, Daniela Galimberti34, Didier Hannequin5, Federico Licastro17, Hilkka Soininen8, Karen Ritchie13, Hélène Blanché35, Jean-François Dartigues12, Christophe Tzourio22,23, Ivo Gut4, Christine Van Broeckhoven6,7, Annick Alpérovitch22,23, Mark Lathrop4,35 & Philippe Amouyel1,2,3,14
The gene encoding apolipoprotein E (APOE) on chromosome 19 is the only confirmed susceptibility locus for late-onset Alzheimer's disease. To identify other risk loci, we conducted a large genome-wide association study of 2,032 individuals from France with Alzheimer's disease (cases) and 5,328 controls. Markers outside APOE with suggestive evidence of association (P < 10-5) were examined in collections from Belgium, Finland, Italy and Spain totaling 3,978 Alzheimer's disease cases and 3,297 controls. Two loci gave replicated evidence of association: one within CLU (also called APOJ), encoding clusterin or apolipoprotein J, on chromosome 8 (rs11136000, OR = 0.86, 95% CI 0.81–0.90, P = 7.5 
10-9 for combined data) and the other within CR1, encoding the complement component (3b/4b) receptor 1, on chromosome 1 (rs6656401, OR = 1.21, 95% CI 1.14–1.29, P = 3.7 10-9 for combined data). Previous biological studies support roles of CLU and CR1 in the clearance of 
amyloid (A) peptide, the principal constituent of amyloid plaques, which are one of the major brain lesions of individuals with Alzheimer's disease.
- Inserm U744, Lille, France.
- Institut Pasteur de Lille, Lille, France.
- Université de Lille Nord de France, Lille, France.
- Centre National de Génotypage, Institut Genomique, Commissariat à l'énergie Atomique, Evry, France.
- Inserm U614, Faculté de Médecine-Pharmacie de Rouen, Rouen, France.
- Neurodegenerative Brain Diseases group, Department of Molecular Genetics, VIB, Antwerpen, Belgium.
- Institute Born-Bunge and University of Antwerp, Antwerpen, Belgium.
- Department of Neurology, Kuopio University and University Hospital, Finland.
- Neurology Service and Centro Investigación Biomédica en Red para Enfermedades Neurodegenerativas (CIBERNED), 'Marqués de Valdecilla' University Hospital, University of Cantabria, Santander, Spain.
- Centro de Biologia Molecular Severo Ochoa, Universidad Autónoma de Madrid–Consejo Superior de Investigaciones Científicas and CIBERNED, Universidad Autonoma, Cantoblanco, Madrid, Spain.
- Departement de Geriatrie, Centre Hospitalier Universitaire de Dijon, Dijon, France.
- Inserm U897, Victor Segalen University, Bordeaux, France.
- Inserm U888, Hôpital La Colombière, Montpellier, France.
- Centre Hospitalier Régional Universitaire de Lille, Lille, France.
- Memory Clinic and Department of Neurology, Ziekenhuisnetwerk Antwerpen Middelheim, Antwerpen, Belgium.
- Servicio de Neurologia, Hospital Universitario La Paz, Universidad Autónoma de Madrid and CIBERNED, Madrid, Spain.
- Department of Experimental Pathology, School of Medicine, University of Bologna, Italy.
- Inserm U894 Faculté de Médecine, Université Paris Descartes, Paris, France.
- A full list of members is provided in the Supplementary Note.
- Banco de ADN, Universidad del Pais Vasco(UPV/EHU), Facultad de Farmacia, Vitoria-Gasteiz, Spain.
- Molecular Psychiatry Laboratory, Queensland Institute of Medical Research, Royal Brisbane Hospital, Queensland, Australia.
- Inserm U708, Paris, France.
- Université Pierre et Marie Curie Paris 6, Paris, France.
- Department of genetics, Institut de la vision, Inserm, Université Pierre et Marie Curie Paris 6, Paris, France.
- Genetic Molecular Unit, Hospital Universitario Central de Asturias, Oviedo, Spain.
- Istituto Di Ricovero e Cura a Carattere Scientifico (IRCCS) Associazione Oasi Maria Santissima, Institute for Research on Mental Retardation and Brain Aging, Troina, Italy.
- Department of Neuroscience, Neurological Clinic, University of Pisa, Italy.
- Department of Geriatrics, Center for Aging Brain, Memory Unit, University of Bari, Bari, Italy.
- Department of Neurological and Psychiatric Sciences, Florence, Italy.
- Department of Clinical and Behavioral Neurology, IRCCS Santa Lucia Foundation, Roma, Italy.
- Laboratory of Molecular Genetics, Section of Clinical Pharmacology, Department of Neuroscience, University of Cagliari, Italy.
- Department of Clinical Medicine and Prevention, University of Milano-Bicocca, Monza, Italy.
- Geriatric Unit & Gerontology-Geriatric Research Laboratory, Department of Medical Science, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy.
- Department of Neurological Sciences, Dino Ferrari Center, University of Milan, IRCCS Ospedale Maggiore Policlinico, Milan, Italy.
- Fondation Jean Dausset–Centre d'Etudes du Polymorphisme Humain, Paris, France.
Correspondence to: Philippe Amouyel1,2,3,14 e-mail: philippe.amouyel@pasteur-lille.fr
