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Title
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Alzheimer risk associated with a copy number variation in the complement receptor 1 increasing C3b/C4b binding sites
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Author
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Abstract
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| Two multicentre genome-wide association (GWA) studies provided substantial evidence, implicating the complement receptor 1 gene (CR1) in Alzheimer disease (AD) genetic etiology. CR1 encodes a large transmembrane receptor with a crucial role in the immune complement cascade. We performed a genetic follow-up of the GWA CR1 association in a FlandersBelgian cohort (n=1883), and investigated the effect of single-nucleotide polymorphisms (SNPs) located in the CR1 locus on AD risk and cerebrospinal fluid (CSF) biomarker levels. We obtained significant association (Padj<0.03; odds ratio (OR)=1.24 (95% confidence interval (CI): 1.021.51)) for one CR1 risk haplotype, and haplotype association was strongest in individuals carrying apolipoprotein E (APOE) ε4 alleles (Padj<0.006; OR=1.50 (95% CI: 1.082.09)). Also, four SNPs correlated with increased CSF amyloid Aβ1−42 levels, suggesting a role for the CR1 protein in Aβ metabolism. Moreover, we quantified a low-copy repeat (LCR)-associated copy number variation (CNV) in CR1, producing different CR1 isoforms, CR1-F and CR1-S, and obtained significant association in carriers of CR1-S. We replicated the CR1 CNV association finding in a French cohort (n=2003) and calculated in the combined cohorts, an OR of 1.32; 95% CI: 1.101.59 (P=0.0025). Our data showed that the common AD risk association may well be explained by the presence of CR1-S increasing the number of C3b/C4b and cofactor activity sites and AD risk with 30% in CR1-S carriers. How precisely the different functional role of CR1-S in the immune complement cascade contributes to AD pathogenesis will need additional functional studies. |
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Language
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English
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Source (journal)
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Molecular psychiatry. - London
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Publication
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London
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2012
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ISSN
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1359-4184
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DOI
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10.1038/MP.2011.24
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Volume/pages
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17
:2
(2012)
, p. 223-233
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ISI
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000299802400015
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Full text (Publisher's DOI)
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Full text (publisher's version - intranet only)
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