Alzheimer risk associated with a copy number variation in the complement receptor 1 increasing C3b/C4b binding sites

Mol Psychiatry. 2012 Feb;17(2):223-33. doi: 10.1038/mp.2011.24. Epub 2011 Mar 15.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Alzheimer Disease / cerebrospinal fluid
  • Alzheimer Disease / genetics*
  • Amyloid beta-Peptides / cerebrospinal fluid
  • Apolipoprotein E4 / genetics
  • Cohort Studies
  • Complement Factor I / metabolism*
  • DNA Copy Number Variations / genetics*
  • Female
  • Gene Frequency
  • Genome-Wide Association Study
  • Genotype
  • Humans
  • Logistic Models
  • Male
  • Meta-Analysis as Topic
  • Odds Ratio
  • Peptide Fragments / cerebrospinal fluid
  • Polymorphism, Single Nucleotide / genetics*
  • Receptors, Complement / genetics*
  • Segmental Duplications, Genomic
  • tau Proteins / cerebrospinal fluid


  • Amyloid beta-Peptides
  • Apolipoprotein E4
  • Peptide Fragments
  • Receptors, Complement
  • amyloid beta-protein (1-42)
  • tau Proteins
  • Complement Factor I