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, 17 (2), 223-33

Alzheimer Risk Associated With a Copy Number Variation in the Complement Receptor 1 Increasing C3b/C4b Binding Sites

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Alzheimer Risk Associated With a Copy Number Variation in the Complement Receptor 1 Increasing C3b/C4b Binding Sites

N Brouwers et al. Mol Psychiatry.

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.

Figures

Figure 1
Figure 1
Genomic architecture of the CR1 locus in relation to the major CR1 isoforms. The upper triangle shows a dot plot of the self-alignment of the genomic region (5′ to 3′) encompassing the genes CR1 and CR1-like (CR1L). Dot plot colors represent sequence identity. Low-copy repeats (LCRs) are represented as horizontal arrows below the dot plot. The genomic segment is graphically annotated at different levels below the dot plot. Annotation is given for the two major CR1 isoforms CR1-S and CR1-F. LCRs: arrows indicate location and orientation of the LCRs. The LCR present at variable number of copies, resulting in the CR1 isoforms indicated with pink arrows. Multiplex amplicon quantification (MAQ) ampl: location of amplicons 1–4, used for the CR1 LCR dosage analysis. Gene: location and exon structure of CR1 and CR1L. Transcript: organization of the CR1 transcripts. Boxes represent exons with wide regions representing coding sequences and narrow regions untranslated sequences (UTRs). Arrows show the organization of the long homologous repeat regions (LHRs). The open box labeled TM denotes the region encoding the transmembrane domain. Protein: CR1 functional domains with each circle representing a separate short consensus repeat. The first three short consensus repeats in LHR A, S, B and C are required for complement factor binding and inhibitory activity (decay accelerating activity or cofactor activity), in which the first two determine factor-binding specificity and the type of inhibition, indicated by different hatching patterns.
Figure 2
Figure 2
LD structure of the CR1 locus and single single-nucleotide polymorphism (SNP) allelic association in AD. Allelic associations corrected for age (onset/inclusion), gender and APOE ɛ4 genotype (for analyses not stratified for APOE ɛ4 genotype) are plotted as −log10(P). SNPs are placed in the graph according to their position in CR1 shown below the graph. The lower panel of the figure shows the pairwise linkage disequilibrium pattern between SNPs as measured by their r2 values.
Figure 3
Figure 3
Association of SNP genotypes with Aβ1−42 cerebrospinal fluid (CSF) levels. CSF Aβ1−42 levels (pg ml−1) measured in patients carrying different single-nucleotide polymorphism (SNP) genotypes. Because of high r2 values between rs646817 and rs1746659, and between rs12034383 and rs11803956, only results for rs646817 and rs12034383 are shown. Significant pairwise comparisons are indicated, that is, AA vs AG+GG for rs646817 and AA vs GG for rs12034383, with P-values corrected for age at lumbar puncture, disease duration at lumbar puncture, gender and APOE ɛ4 genotype. For rs646817, results of the association test under a dominant model are depicted.
Figure 4
Figure 4
CR1 LCR dosage and CR1 isoform analysis. (a) Dosage analysis of the low-copy repeats (LCRs) underlying CR1 isoforms in selected individuals. Colored dashed lines connect dosage quotient values obtained with multiplex amplicon quantification (MAQ) amplicons specific for the CR1 LCRs (amplicons 1–3) (Figure 1) referred to by encircled numbers and three representative reference amplicons. The graph legend shows the isoforms predicted to be encoded by the CR1 copy number variation (CNV) genotype. The size of the symbols indicates the relative abundance of the respective CNV genotype. (b) Anti-CR1 immunoblot analysis of selected individuals illustrating the correlation between CNV genotype and protein isoforms. Lanes are grouped per number of copies of LCR1 present (Table 1).

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