Both common variations and rare non-synonymous substitutions and small insertion/deletions in CLU are associated with increased Alzheimer risk
Bettens K, Brouwers N, Engelborghs S, Lambert JC, Rogaeva E, Vandenberghe R, Le Bastard N, Pasquier F et al.. Molecular neurodegeneration, 2012-01-16
Topic: Amyloid, tau and blood-test diagnosis
Background We have followed-up on the recent genome-wide association (GWA) of the clusterin gene (CLU) with increased risk for Alzheimer disease (AD), by performing an unbiased resequencing of all CLU coding exons and regulatory regions in an extended Flanders-Belgian cohort of Caucasian AD patients and control individuals (n = 1930). Moreover, we have replicated genetic findings by targeted resequencing in independent Caucasian cohorts of French (n = 2182) and Canadian (n = 573) origin and by performing meta-analysis combining our data with previous genetic CLU screenings. Results In the Flanders-Belgian cohort, we identified significant clustering in exons 5-8 of rare genetic variations leading to non-synonymous substitutions and a 9-bp insertion/deletion affecting the CLU β-chain (p = 0.02). Replicating this observation by targeted resequencing of CLU exons 5-8 in 2 independent Caucasian cohorts of French and Canadian origin identified identical as well as novel non-synonymous substitutions and small insertion/deletions. A meta-analysis, combining the datasets of the 3 cohorts with published CLU sequencing data, confirmed that rare coding variations in the CLU β-chain were significantly enriched in AD patients (OR(MH) = 1.96 [95% CI = 1.18-3.25]; p = 0.009). Single nucleotide polymorphisms (SNPs) association analysis indicated the common AD risk association (GWA SNP rs11136000, p = 0.013) in the 3 combined datasets could not be explained by the presence of the rare coding variations we identified. Further, high-density SNP mapping in the CLU locus mapped the common association signal to a more 5' CLU region. Conclusions We identified a new genetic risk association of AD with rare coding CLU variations that is independent of the 5' common association signal identified in the GWA studies. At this stage the role of these coding variations and their likely effect on the β-chain domain and CLU protein functioning remains unclear and requires further studies.
Cite this study APA, Vancouver, BibTeX · download .bib or .ris
APA 7th
Bettens, K., Brouwers, N., Engelborghs, S., Lambert, J. C., Rogaeva, E., Vandenberghe, R., et al. (2012). Both common variations and rare non-synonymous substitutions and small insertion/deletions in CLU are associated with increased Alzheimer risk. Molecular neurodegeneration. https://doi.org/10.1186/1750-1326-7-3
Vancouver
Bettens K, Brouwers N, Engelborghs S, Lambert JC, Rogaeva E, Vandenberghe R, et al. Both common variations and rare non-synonymous substitutions and small insertion/deletions in CLU are associated with increased Alzheimer risk. Molecular neurodegeneration. 2012. doi:10.1186/1750-1326-7-3. PMID: 22248099.
BibTeX
@article{bettens2012-22248099,
author = {Bettens, K. and Brouwers, N. and Engelborghs, S. and Lambert, J. C. and Rogaeva, E. and Vandenberghe, R. and Le Bastard, N. and Pasquier, F. and others},
title = {{Both common variations and rare non-synonymous substitutions and small insertion/deletions in CLU are associated with increased Alzheimer risk}},
journal = {Molecular neurodegeneration},
year = {2012},
doi = {10.1186/1750-1326-7-3},
pmid = {22248099},
url = {https://doi.org/10.1186/1750-1326-7-3}
}
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.
Key findings
- Background We have followed-up on the recent genome-wide association (GWA) of the clusterin gene (CLU) with increased risk for Alzheimer disease (AD), by performing an unbiased resequencing of all CLU coding exons and regulatory regions in an extended Flanders-Belgian cohort of Caucasian AD patients and control individuals (n = 1930).
- Results In the Flanders-Belgian cohort, we identified significant clustering in exons 5-8 of rare genetic variations leading to non-synonymous substitutions and a 9-bp insertion/deletion affecting the CLU β-chain (p = 0.02).
- A meta-analysis, combining the datasets of the 3 cohorts with published CLU sequencing data, confirmed that rare coding variations in the CLU β-chain were significantly enriched in AD patients (OR(MH) = 1.96 [95% CI = 1.18-3.25]; p = 0.009).
Why it matters
This genetic study found that both common and rare variations in the CLU gene were associated with increased risk of Alzheimer disease across several cohorts. These are risk associations only and do not provide a treatment or cure.
New to this subject? Start with our plain-English guide: Genetics →
Study details
- Study designmeta-analysis
- Participants1,930
- Evidence strengthHigh
Limitations
The core finding comes from one Belgian cohort; the abstract does not state whether these specific rare variants, as opposed to the general CLU association, were confirmed in the independent French and Canadian replication cohorts.
How this study scored 68/100
Published in a peer-reviewed journal, and it is a meta-analysis pooling many studies. Scored zero for effect reported because the record does not state it.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Molecular neurodegeneration) |
| Journal's citation record | 2 / 4 | Molecular Neurodegeneration: journal h-index 164 (OpenAlex, 2026-10-29) |
| Study design | 12 / 12 | A meta-analysis pooling many studies |
| Strength of evidence | 5 / 5 | Rated “high” 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 | 1,930 participants |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 3 / 3 | Studied in people (participant count stated) |
| Randomised / blinded | 0 / 2 | A review of other studies — randomisation is not credited here |
| Times cited | 4 / 7 | Cited 95 times (OpenAlex, 2026-10-10) |
| Citations per year | 2 / 5 | 5.9 citations a year over 16 year(s) since 2012 |
| Impact for its field and year | 3 / 6 | Cited 6.1× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 2 / 6 | Cited by 6 other studies in this library |
| Still being cited | 1 / 4 | Cited 4 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 | 3 / 3 | OpenAlex lists 11 institution(s) in 5 countries |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 22248099) |
| Free to read | 2 / 2 | Free to read |
| Total | 68 / 100 | — |
What each of these 20 components measures, and what this score is not →
Read the original
- DOI: 10.1186/1750-1326-7-3
- PubMed: 22248099
- Original source →
- Free full text: Molecular Neurodegeneration →
Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).
Studies this one cites
Referenced by this study and also in the alzhub library, so you can read them here. Showing 12 of 13.
Later studies that cite this one
6 studies in the alzhub library list this one in their references.
Related studies in Genetics
Also tagged “precursor”
1,339 studies in the library carry the topic tag “precursor”; 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.