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 β amyloid (Aβ) peptide, the principal constituent of amyloid plaques, which are one of the major brain lesions of individuals with Alzheimer's disease.
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The work was made possible by the generous participation of the control subjects, the subjects with Alzheimer's disease, and their families. We thank A. Boland (Centre National de Génotypage) for her technical help in preparing the DNA samples for analyses. This work was supported by the National Foundation for Alzheimer's Disease and Related Disorders, the Institut Pasteur de Lille and the Centre National de Génotypage.
The Three-City Study was performed as part of a collaboration between the Institut National de la Santé et de la Recherche Médicale (Inserm), the Victor Segalen Bordeaux II University and Sanofi-Synthélabo. The Fondation pour la Recherche Médicale funded the preparation and initiation of the study. The 3C Study was also funded by the Caisse Nationale d'Assurance Maladie des Travailleurs Salariés, Direction Générale de la Santé, Mutuelle Générale de l'Education Nationale, Institut de la Longévité, Agence Française de Sécurité Sanitaire des Produits de Santé, the Aquitaine and Bourgogne Regional Councils, Fondation de France and the joint French Ministry of Research/Inserm 'Cohortes et collections de données biologiques' programme. Lille Génopôle received an unconditional grant from Eisai.
Belgium sample collection: the Antwerp site (CVB) was in part supported by the VIB Genetic Service Facility (http://www.vibgeneticservicefacility.be/) and the Biobank of the Institute Born-Bunge; the Special Research Fund of the University of Antwerp; the Fund for Scientific Research-Flanders (FWO-V); the Foundation for Alzheimer Research (SAO-FRMA); and the Interuniversity Attraction Poles (IAP) program P6/43 of the Belgian Federal Science Policy Office, Belgium; K.S. is a postdoctoral fellow and K.B. a PhD fellow of the FWO-V.
Finnish sample collection: Financial support for this project was provided by the Health Research Council of the Academy of Finland, EVO grant 5772708 of Kuopio University Hospital, and the Nordic Centre of Excellence in Neurodegeneration.
Italian sample collection: the Bologna site (FL) obtained funds from the Italian Ministry of research and University as well as Carimonte Foundation. The Florence site was supported by a grant from the Italian ministry of Health (RFPS-2006-7-334858). The Milan site was supported by a grant from the 'fondazione Monzino'. We appreciate the expert contribution of C. Romano.
Spanish sample collection: the Madrid site (MB) was supported by grants of the Ministerio de Educación y Ciencia and the Ministerio de Sanidad y Consumo (Instituto de Salud Carlos III) and an institutional grant of the Fundación Ramón Areces to the Centro de Biología Molecular Severo Ochoa. We thank I. Sastre and A. Martínez-García for the preparation and control of the DNA collection and P. Gil and P. Coria for their cooperation in the recruitment of cases and controls. We are grateful to the Asociación de Familiares de Alzheimer de Madrid (AFAL) for continuous encouragement and help.
The authors have a patent under consideration based on the findings of this work.
A full list of members is provided in the Supplementary Note.
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