Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer's disease

Philippe Amouyel and colleagues report a genome-wide association study for Alzheimer's disease. They identify variants within CLU and CR1 associated with susceptibility to late-onset Alzheimer's disease. 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.