Whole-exome sequencing in 20,197 persons for rare variants in Alzheimer's disease
Raghavan NS, Brickman AM, Andrews H, Manly JJ, Schupf N, Lantigua R, Wolock CJ, Kamalakaran S et al.. Annals of clinical and translational neurology, 2018-05-24
Topic: Amyloid, tau and blood-test diagnosis
Objective The genetic bases of Alzheimer's disease remain uncertain. An international effort to fully articulate genetic risks and protective factors is underway with the hope of identifying potential therapeutic targets and preventive strategies. The goal here was to identify and characterize the frequency and impact of rare and ultra-rare variants in Alzheimer's disease, using whole-exome sequencing in 20,197 individuals. Methods We used a gene-based collapsing analysis of loss-of-function ultra-rare variants in a case-control study design with data from the Washington Heights-Inwood Columbia Aging Project, the Alzheimer's Disease Sequencing Project and unrelated individuals from the Institute of Genomic Medicine at Columbia University. Results We identified 19 cases carrying extremely rare SORL1 loss-of-function variants among a collection of 6,965 cases and a single loss-of-function variant among 13,252 controls ( P = 2.17 × 10 -8 ; OR: 36.2 [95% CI: 5.8-1493.0]). Age-at-onset was 7 years earlier for patients with SORL1 qualifying variant compared with noncarriers. No other gene attained a study-wide level of statistical significance, but multiple top-ranked genes, including GRID2IP , WDR76 and GRN, were among candidates for follow-up studies. Interpretation This study implicates ultra-rare, loss-of-function variants in SORL1 as a significant genetic risk factor for Alzheimer's disease and provides a comprehensive dataset comparing the burden of rare variation in nearly all human genes in Alzheimer's disease cases and controls. This is the first investigation to establish a genome-wide statistically significant association between multiple extremely rare loss-of-function variants in SORL1 and Alzheimer's disease in a large whole-exome study of unrelated cases and controls.
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APA 7th
Raghavan, N. S., Brickman, A. M., Andrews, H., Manly, J. J., Schupf, N., Lantigua, R., et al. (2018). Whole-exome sequencing in 20,197 persons for rare variants in Alzheimer's disease. Annals of clinical and translational neurology. https://doi.org/10.1002/acn3.582
Vancouver
Raghavan NS, Brickman AM, Andrews H, Manly JJ, Schupf N, Lantigua R, et al. Whole-exome sequencing in 20,197 persons for rare variants in Alzheimer's disease. Annals of clinical and translational neurology. 2018. doi:10.1002/acn3.582. PMID: 30009200.
BibTeX
@article{raghavan2018-30009200,
author = {Raghavan, N. S. and Brickman, A. M. and Andrews, H. and Manly, J. J. and Schupf, N. and Lantigua, R. and Wolock, C. J. and Kamalakaran, S. and others},
title = {{Whole-exome sequencing in 20,197 persons for rare variants in Alzheimer's disease}},
journal = {Annals of clinical and translational neurology},
year = {2018},
doi = {10.1002/acn3.582},
pmid = {30009200},
url = {https://doi.org/10.1002/acn3.582}
}
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Key findings
- Results We identified 19 cases carrying extremely rare SORL1 loss-of-function variants among a collection of 6,965 cases and a single loss-of-function variant among 13,252 controls ( P = 2.17 × 10 -8 ; OR: 36.2 [95% CI: 5.8-1493.0]).
- Age-at-onset was 7 years earlier for patients with SORL1 qualifying variant compared with noncarriers.
- Interpretation This study implicates ultra-rare, loss-of-function variants in SORL1 as a significant genetic risk factor for Alzheimer's disease and provides a comprehensive dataset comparing the burden of rare variation in nearly all human genes in Alzheimer's disease cases and controls.
- This is the first investigation to establish a genome-wide statistically significant association between multiple extremely rare loss-of-function variants in SORL1 and Alzheimer's disease in a large whole-exome study of unrelated cases and controls.
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Study details
- Study designcase-control study
- Participants20,197
- Effect sizeOR: 36.2
- Evidence strengthModerate
How this study scored 72/100
Published in a peer-reviewed journal, and it is a case-control study. Scored zero for randomised / blinded because the record does not state it. We have no data on journal's citation record, times cited, citations per year, impact for its field and year, cited by studies here, still being cited, senior author's track record, institution's track record and multi-centre collaboration, so those were left out: it earned 42 of the 58 points we could judge it on, which is 72 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Annals of clinical and translational neurology) |
| Journal's citation record | — / 4 | No journal record from OpenAlex — left out of this score |
| Study design | 6 / 12 | A case-control study |
| 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 | 2 / 5 | 2018 — within 10 year(s) of the newest study here |
| Sample size | 4 / 4 | 20,197 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 | — / 7 | No citation count (not found in OpenAlex) — left out of this score |
| Citations per year | — / 5 | No citation count or no year — left out of this score |
| Impact for its field and year | — / 6 | No field-weighted citation impact (OpenAlex has none yet) — left out of this score |
| Cited by studies here | — / 6 | Not yet checked against this library's citation graph — left out of this score |
| Still being cited | — / 4 | No yearly citation counts — left out of this score |
| Senior author's track record | — / 4 | Senior author's record not available — left out of this score |
| Institution's track record | — / 3 | No institution listed in OpenAlex — left out of this score |
| Multi-centre collaboration | — / 3 | Institutions not listed — left out of this score |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 30009200) |
| Free to read | 2 / 2 | Free to read |
| Points | 42 / 58 | Scored on 11 of 20 parts. We have no data for the rest, so they are left out: 42 of the 58 points we could judge it on is 72 out of 100. |
| Total | 72 / 100 | — |
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