Topic: Amyloid, tau and blood-test diagnosis
Objective To detect rare coding variants underlying loci detected by genome-wide association studies (GWAS) of late onset Alzheimer disease (LOAD). Methods We conducted targeted sequencing of ABCA7, BIN1, CD2AP, CLU, CR1, EPHA1, MS4A4A/MS4A6A, and PICALM in 3 independent LOAD cohorts: 176 patients from 124 Caribbean Hispanics families, 120 patients and 33 unaffected individuals from the 129 National Institute on Aging LOAD Family Study; and 263 unrelated Canadian individuals of European ancestry (210 sporadic patients and 53 controls). Rare coding variants found in at least 2 data sets were genotyped in independent groups of ancestry-matched controls. Additionally, the Exome Aggregation Consortium was used as a reference data set for population-based allele frequencies. Results Overall we detected a statistically significant 3.1-fold enrichment of the nonsynonymous mutations in the Caucasian LOAD cases compared with controls (p = 0.002) and no difference in synonymous variants. A stop-gain mutation in ABCA7 (E1679X) and missense mutation in CD2AP (K633R) were highly significant in Caucasian LOAD cases, and mutations in EPHA1 (P460L) and BIN1 (K358R) were significant in Caribbean Hispanic families with LOAD. The EPHA1 variant segregated completely in an extended Caribbean Hispanic family and was also nominally significant in the Caucasians. Additionally, BIN1 (K358R) segregated in 2 of the 6 Caribbean Hispanic families where the mutations were discovered. Interpretation Targeted sequencing of confirmed GWAS loci revealed an excess burden of deleterious coding mutations in LOAD, with the greatest burden observed in ABCA7 and BIN1. Identifying coding variants in LOAD will facilitate the creation of tractable models for investigation of disease-related mechanisms and potential therapies.
Key findings
- Results Overall we detected a statistically significant 3.1-fold enrichment of the nonsynonymous mutations in the Caucasian LOAD cases compared with controls (p = 0.002) and no difference in synonymous variants.
- A stop-gain mutation in ABCA7 (E1679X) and missense mutation in CD2AP (K633R) were highly significant in Caucasian LOAD cases, and mutations in EPHA1 (P460L) and BIN1 (K358R) were significant in Caribbean Hispanic families with LOAD.
- The EPHA1 variant segregated completely in an extended Caribbean Hispanic family and was also nominally significant in the Caucasians.
- Interpretation Targeted sequencing of confirmed GWAS loci revealed an excess burden of deleterious coding mutations in LOAD, with the greatest burden observed in ABCA7 and BIN1.
Why it matters
This sequencing study found a 3.1-fold enrichment of nonsynonymous mutations in Caucasian late-onset Alzheimer's cases compared with controls, with specific mutations in ABCA7, CD2AP, EPHA1 and BIN1 being significant. It supports the idea that rare coding variants in known risk genes contribute to the disease.
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Study details
- Participants176
- Evidence strengthLow
How this study scored 58/100
Published in a leading specialty journal. Scored zero for study design, effect reported and randomised / blinded because the record does not state it.
| Component | Points | Why |
|---|---|---|
| Journal tier | 9 / 10 | Tier 2 — leading specialty journal (Annals of neurology) |
| Journal's citation record | 3 / 4 | Annals of Neurology: journal h-index 437 (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 | 1 / 5 | Rated “low” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 1 / 5 | 2015 — within 20 year(s) of the newest study here |
| Sample size | 2 / 4 | 176 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 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 5 / 7 | Cited 149 times (OpenAlex, 2026-10-10) |
| Citations per year | 3 / 5 | 11.5 citations a year over 13 year(s) since 2015 |
| Impact for its field and year | 4 / 6 | Cited 15.1× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 3 / 6 | Cited by 10 other studies in this library |
| Still being cited | 2 / 4 | Cited 26 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 4 / 4 | Last-listed author Richard P Mayeux: h-index 158 (OpenAlex, whole career) |
| Institution's track record | 2 / 3 | University of Cambridge: institution h-index 1,973 (OpenAlex) |
| Multi-centre collaboration | 2 / 3 | OpenAlex lists 7 institution(s) in 5 countries |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 26101835) |
| Free to read | 2 / 2 | Free to read |
| Total | 58 / 100 | — |
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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
Vardarajan, B. N., Ghani, M., Kahn, A., Sheikh, S., Sato, C., Barral, S., et al. (2015). Rare coding mutations identified by sequencing of Alzheimer disease genome-wide association studies loci. Annals of neurology. https://doi.org/10.1002/ana.24466
Vancouver
Vardarajan BN, Ghani M, Kahn A, Sheikh S, Sato C, Barral S, et al. Rare coding mutations identified by sequencing of Alzheimer disease genome-wide association studies loci. Annals of neurology. 2015. doi:10.1002/ana.24466. PMID: 26101835.
BibTeX
@article{vardarajan2015-26101835,
author = {Vardarajan, B. N. and Ghani, M. and Kahn, A. and Sheikh, S. and Sato, C. and Barral, S. and Lee, J. H. and Cheng, R. and others},
title = {{Rare coding mutations identified by sequencing of Alzheimer disease genome-wide association studies loci}},
journal = {Annals of neurology},
year = {2015},
doi = {10.1002/ana.24466},
pmid = {26101835},
url = {https://doi.org/10.1002/ana.24466}
}
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