title: Genetic association of CR1 with Alzheimer's disease: a tentative disease mechanism.
abstract: CR1 is a novel Alzheimer's disease (AD) gene identified by genome-wide association studies (GWAS). Recently, we showed that AD risk could be explained by an 18-kilobase insertion responsible for the complement component (3b/4b) receptor 1 (CR1)-S isoform. We investigated the relevance of the CR1 isoforms to AD in a Canadian dataset. Also, we genotyped rs4844610 tagging the GWAS-significant CR1 single nucleotide polymorphisms. Individuals with F/S genotype had a 1.8 times increased risk for AD compared with F/F genotype (p-adjusted = 0.003), while rs4844610 was only marginally significant (p-adjusted = 0.024). The analyses of brain samples demonstrated that the CR1-S isoform is expressed at lower protein levels than CR1-F (p < 0.0001) hence likely associated with increased complement activation. Intriguingly, our neuropathological results show that the pattern of CR1 expression in neurons is different between the F/F and F/S genotypes (filiform vs. vesicular-like profiles). Furthermore, double labeling studies supported a differential distribution of CR1 in neurons (endoplasmic reticulum intermediate compartment vs. lysosomes). These observations indicate that the CR1-S and CR1-F isoforms could be processed in different ways in neurons. In conclusion, our results support that the CR1-S isoform explains the GWAS signals and open a novel prospect for the investigation of CR1-related disease mechanisms.
authors: Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario, Canada.
authors: Lili-Naz
authors: LN
authors: Hazrati
authors: Caroline
authors: C
authors: Van Cauwenberghe
authors: Patricia L
authors: PL
authors: Brooks
authors: Nathalie
authors: N
authors: Brouwers
authors: Mahdi
authors: M
authors: Ghani
authors: Christine
authors: C
authors: Sato
authors: Marc
authors: M
authors: Cruts
authors: Kristel
authors: K
authors: Sleegers
authors: Peter
authors: P
authors: St George-Hyslop
authors: Christine
authors: C
authors: Van Broeckhoven
authors: Ekaterina
authors: E
authors: Rogaeva
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism; D053327:Apolipoprotein E4 / Q000235:genetics; D002170:Canada; D016009:Chi-Square Distribution; D015331:Cohort Studies; D056915:DNA Copy Number Variations / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D017463:Receptors, Complement 3b / Q000235:genetics* / Q000378:metabolism
chemical_list: D053327:Apolipoprotein E4; C509991:CR1 protein, human; D020033:Protein Isoforms; D017463:Receptors, Complement 3b