title: Alzheimer risk associated with a copy number variation in the complement receptor 1 increasing C3b/C4b binding sites.
abstract: 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 Flanders-Belgian 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 (P(adj)<0.03; odds ratio (OR)=1.24 (95% confidence interval (CI): 1.02-1.51)) for one CR1 risk haplotype, and haplotype association was strongest in individuals carrying apolipoprotein E (APOE) ɛ4 alleles (P(adj)<0.006; OR=1.50 (95% CI: 1.08-2.09)). 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: 1.10-1.59 (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.
authors.affiliation: Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB, Antwerpen, Belgium.
authors.forename: N
authors.initials: N
authors.lastname: Brouwers
authors.forename: C
authors.initials: C
authors.lastname: Van Cauwenberghe
authors.forename: S
authors.initials: S
authors.lastname: Engelborghs
authors.forename: J-C
authors.initials: JC
authors.lastname: Lambert
authors.forename: K
authors.initials: K
authors.lastname: Bettens
authors.forename: N
authors.initials: N
authors.lastname: Le Bastard
authors.forename: F
authors.initials: F
authors.lastname: Pasquier
authors.forename: A Gil
authors.initials: AG
authors.lastname: Montoya
authors.forename: K
authors.initials: K
authors.lastname: Peeters
authors.forename: M
authors.initials: M
authors.lastname: Mattheijssens
authors.forename: R
authors.initials: R
authors.lastname: Vandenberghe
authors.forename: P P De
authors.initials: PP
authors.lastname: Deyn
authors.forename: M
authors.initials: M
authors.lastname: Cruts
authors.forename: P
authors.initials: P
authors.lastname: Amouyel
authors.forename: K
authors.initials: K
authors.lastname: Sleegers
authors.forename: C
authors.initials: C
authors.lastname: Van Broeckhoven
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid / Q000235:genetics*; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid; D053327:Apolipoprotein E4 / Q000235:genetics; D015331:Cohort Studies; D017244:Complement Factor I / Q000378:metabolism*; D056915:DNA Copy Number Variations / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D016015:Logistic Models; D008297:Male; D015201:Meta-Analysis as Topic; D016017:Odds Ratio; D010446:Peptide Fragments / Q000134:cerebrospinal fluid; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011951:Receptors, Complement / Q000235:genetics*; D056916:Segmental Duplications, Genomic; D016875:tau Proteins / Q000134:cerebrospinal fluid
chemical_list: D016229:Amyloid beta-Peptides; D053327:Apolipoprotein E4; D010446:Peptide Fragments; D011951:Receptors, Complement; C075222:amyloid beta-protein (1-42); D016875:tau Proteins; D017244:Complement Factor I