Alzheimer risk associated with a copy number variation in the complement receptor 1 increasing C3b/C4b binding sites
Brouwers N, Van Cauwenberghe C, Engelborghs S, Lambert JC, Bettens K, Le Bastard N, Pasquier F, Montoya AG et al.. Molecular psychiatry, 2011-03-15
Topic: Amyloid, tau and blood-test diagnosis
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.
Key findings
- 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)).
- 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.
- 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.
Why it matters
This genetic follow-up found association between a CR1 risk haplotype and Alzheimer disease, strongest in APOE epsilon4 carriers, and a CR1 copy number variation producing different CR1 isoforms was also associated with risk. The findings implicate CR1 in Alzheimer disease genetic risk and possibly amyloid metabolism, but no treatment or cure is provided.
New to this subject? Start with our plain-English guide: Genetics →
Study details
- Participants1,883
- Effect sizeOR=1.50 (95% CI: 1.08-2.09)
- Evidence strengthModerate
How this study scored 64/100
Published in a leading specialty journal. Scored zero for study design and randomised / blinded because the record does not state it.
| Component | Points | Why |
|---|---|---|
| Journal tier | 9 / 10 | Tier 2 — leading specialty journal (Molecular psychiatry) |
| Journal's citation record | 3 / 4 | Molecular Psychiatry: journal h-index 318 (OpenAlex, 2026-10-29) |
| Study design | 0 / 12 | No study design recorded — scores zero, not guessed (not stated in the record — scored 0) |
| Strength of evidence | 3 / 5 | Rated “moderate” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 1 / 5 | 2012 — within 20 year(s) of the newest study here |
| Sample size | 3 / 4 | 1,883 participants |
| Effect reported | 3 / 3 | Effect reported with a statistic (interval, p-value, ratio or similar) |
| Studied in people | 3 / 3 | Studied in people (participant count stated) |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 5 / 7 | Cited 227 times (OpenAlex, 2026-10-10) |
| Citations per year | 3 / 5 | 14.2 citations a year over 16 year(s) since 2012 |
| Impact for its field and year | 4 / 6 | Cited 12.0× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 3 / 6 | Cited by 17 other studies in this library |
| Still being cited | 2 / 4 | Cited 36 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 4 / 4 | Last-listed author Christine Van Broeckhoven: h-index 140 (OpenAlex, whole career) |
| Institution's track record | 2 / 3 | Inserm: institution h-index 1,988 (OpenAlex) |
| Multi-centre collaboration | 2 / 3 | OpenAlex lists 9 institution(s) in 2 countries |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 21403675) |
| Free to read | 2 / 2 | Free to read |
| Total | 64 / 100 | — |
What each of these 20 components measures, and what this score is not →
Read the original
Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).
Cite this study APA, Vancouver, BibTeX · download .bib or .ris
Built from the record alzhub holds for this paper, not looked up. Volume, issue and page numbers are not held in the record. The record's author list ends in “et al.”, so not every author is named. Check the citation against the original before you use it.
APA 7th
Brouwers, N., Van Cauwenberghe, C., Engelborghs, S., Lambert, J. C., Bettens, K., Le Bastard, N., et al. (2012). Alzheimer risk associated with a copy number variation in the complement receptor 1 increasing C3b/C4b binding sites. Molecular psychiatry. https://doi.org/10.1038/mp.2011.24
Vancouver
Brouwers N, Van Cauwenberghe C, Engelborghs S, Lambert JC, Bettens K, Le Bastard N, et al. Alzheimer risk associated with a copy number variation in the complement receptor 1 increasing C3b/C4b binding sites. Molecular psychiatry. 2012. doi:10.1038/mp.2011.24. PMID: 21403675.
BibTeX
@article{brouwers2012-21403675,
author = {Brouwers, N. and Van Cauwenberghe, C. and Engelborghs, S. and Lambert, J. C. and Bettens, K. and Le Bastard, N. and Pasquier, F. and Montoya, A. G. and others},
title = {{Alzheimer risk associated with a copy number variation in the complement receptor 1 increasing C3b/C4b binding sites}},
journal = {Molecular psychiatry},
year = {2012},
doi = {10.1038/mp.2011.24},
pmid = {21403675},
url = {https://doi.org/10.1038/mp.2011.24}
}
Studies this one cites
Referenced by this study and also in the alzhub library, so you can read them here.
Later studies that cite this one
17 studies in the alzhub library list this one in their references. Showing the 8 highest-scoring.
Related studies in Genetics
Also tagged “amyloid-beta”
1,339 studies in the library carry the topic tag “amyloid-beta”; these are this study's neighbours in a fixed, alphabetical-by-hash tour of them, not the closest in content. All 1,339 tagged studies.