O1‐01‐06: Risk For Alzheimer's Associated with a Copy Number Variation In The Complement Receptor 1 Increasing C3b/C4b Binding Sites

Two multicentre genome-wide association (GWA) studies provided substantial evidence implicating the complement receptor 1 gene (CR1) in Alzheimer's 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. Moreover, we quantified a low copy repeat (LCR) associated copy number variation (CNV) in CR1 producing different CR1 isoforms, CR1-F and CR1-S. To further strengthen our study we replicated our findings in an additional cohort of French individuals (n=2003). We obtained significant association (padj<0.03; OR=1.24 (95%, CI: 1.02-1.51)) for one CR1 risk haplotype, which was strongest in individuals carrying apolipoprotein E (APOE) ∊4 alleles (padj<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. Quantification of the CR1 CNV obtained significant association in carriers of CR1-S. We replicated the CR1 CNV association finding in a French cohort 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 at het CR1 locus may well be explained by the presence of CR1-S increasing the number of C3b/C4b and CA 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.