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Linkage, whole genome sequence, and biological data implicate variants in RAB10 in Alzheimer's disease resilience
Ridge PG, Karch CM, Hsu S, Arano I, Teerlink CC, Ebbert MTW, Gonzalez Murcia JD, Farnham JM et al.. Genome medicine, 2017-11-29
Topic: Genetics and APOE
Background While age and the APOE ε4 allele are major risk factors for Alzheimer's disease (AD), a small percentage of individuals with these risk factors exhibit AD resilience by living well beyond 75 years of age without any clinical symptoms of cognitive decline. Methods We used over 200 "AD resilient" individuals and an innovative, pedigree-based approach to identify genetic variants that segregate with AD resilience. First, we performed linkage analyses in pedigrees with resilient individuals and a statistical excess of AD deaths. Second, we used whole genome sequences to identify candidate SNPs in significant linkage regions. Third, we replicated SNPs from the linkage peaks that reduced risk for AD in an independent dataset and in a gene-based test. Finally, we experimentally characterized replicated SNPs. Results Rs142787485 in RAB10 confers significant protection against AD (p value = 0.0184, odds ratio = 0.5853). Moreover, we replicated this association in an independent series of unrelated individuals (p value = 0.028, odds ratio = 0.69) and used a gene-based test to confirm a role for RAB10 variants in modifying AD risk (p value = 0.002). Experimentally, we demonstrated that knockdown of RAB10 resulted in a significant decrease in Aβ42 (p value = 0.0003) and in the Aβ42/Aβ40 ratio (p value = 0.0001) in neuroblastoma cells. We also found that RAB10 expression is significantly elevated in human AD brains (p value = 0.04). Conclusions Our results suggest that RAB10 could be a promising therapeutic target for AD prevention. In addition, our gene discovery approach can be expanded and adapted to other phenotypes, thus serving as a model for future efforts to identify rare variants for AD and other complex human diseases.
Key findings
- Second, we used whole genome sequences to identify candidate SNPs in significant linkage regions.
- Results Rs142787485 in RAB10 confers significant protection against AD (p value = 0.0184, odds ratio = 0.5853).
- Experimentally, we demonstrated that knockdown of RAB10 resulted in a significant decrease in Aβ42 (p value = 0.0003) and in the Aβ42/Aβ40 ratio (p value = 0.0001) in neuroblastoma cells.
- We also found that RAB10 expression is significantly elevated in human AD brains (p value = 0.04).
- Conclusions Our results suggest that RAB10 could be a promising therapeutic target for AD prevention.
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Study details
- Evidence strengthLow
How this study scored 41/100
Published in a peer-reviewed journal. Scored zero for study design, sample size, effect reported, studied in people and 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 24 of the 58 points we could judge it on, which is 41 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Genome medicine) |
| Journal's citation record | — / 4 | No journal record from OpenAlex — left out of this score |
| 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 | 2 / 5 | 2017 — within 10 year(s) of the newest study here |
| Sample size | 0 / 4 | Participant count not stated — scores zero (not stated in the record — scored 0) |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 0 / 3 | Not stated whether this was studied in people — scores zero (not stated in the record — scored 0) |
| 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 29183403) |
| Free to read | 2 / 2 | Free to read |
| Points | 24 / 58 | Scored on 11 of 20 parts. We have no data for the rest, so they are left out: 24 of the 58 points we could judge it on is 41 out of 100. |
| Total | 41 / 100 | — |
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APA 7th
Ridge, P. G., Karch, C. M., Hsu, S., Arano, I., Teerlink, C. C., Ebbert, M. T. W., et al. (2017). Linkage, whole genome sequence, and biological data implicate variants in RAB10 in Alzheimer's disease resilience. Genome medicine. https://doi.org/10.1186/s13073-017-0486-1
Vancouver
Ridge PG, Karch CM, Hsu S, Arano I, Teerlink CC, Ebbert MTW, et al. Linkage, whole genome sequence, and biological data implicate variants in RAB10 in Alzheimer's disease resilience. Genome medicine. 2017. doi:10.1186/s13073-017-0486-1. PMID: 29183403.
BibTeX
@article{ridge2017-29183403,
author = {Ridge, P. G. and Karch, C. M. and Hsu, S. and Arano, I. and Teerlink, C. C. and Ebbert, M. T. W. and Gonzalez Murcia, J. D. and Farnham, J. M. and others},
title = {{Linkage, whole genome sequence, and biological data implicate variants in RAB10 in Alzheimer's disease resilience}},
journal = {Genome medicine},
year = {2017},
doi = {10.1186/s13073-017-0486-1},
pmid = {29183403},
url = {https://doi.org/10.1186/s13073-017-0486-1}
}
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