Topic: Genetics and APOE
Alzheimer's disease (AD) is the most common multifactorial neurodegenerative disease among elderly people. Genome-wide association studies (GWAS) have been highly successful in identifying genetic risk factors. However, GWAS investigate common variants, which tend to have small effect sizes, and rare variants with potentially larger phenotypic effects have not been sufficiently investigated. Whole-genome sequencing (WGS) enables us to detect those rare variants. Here, we performed rare-variant association studies by using WGS data from 140 individuals with probable AD and 798 cognitively normal elder controls (CN), as well as single-nucleotide polymorphism genotyping data from an independent large Japanese AD cohort of 1604 AD and 1235 CN subjects. We identified two rare variants as candidates for AD association: a missense variant in OR51G1 (rs146006146, c.815 G > A, p.R272H) and a stop-gain variant in MLKL (rs763812068, c.142 C > T, p.Q48X). Subsequent in vitro functional analysis revealed that the MLKL stop-gain variant can contribute to increases not only in abnormal cells that should die by programmed cell death but do not, but also in the ratio of Aβ42 to Aβ40. We further detected AD candidate genes through gene-based association tests of rare variants; a network-based meta-analysis using these candidates identified four functionally important hub genes (NCOR2, PLEC, DMD, and NEDD4). Our findings will contribute to the understanding of AD and provide novel insights into its pathogenic mechanisms that can be used in future studies.
Key findings
- Subsequent in vitro functional analysis revealed that the MLKL stop-gain variant can contribute to increases not only in abnormal cells that should die by programmed cell death but do not, but also in the ratio of Aβ42 to Aβ40.
- Our findings will contribute to the understanding of AD and provide novel insights into its pathogenic mechanisms that can be used in future studies.
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Study details
- Study designmeta-analysis
- Participants140
- Evidence strengthHigh
How this study scored 82/100
Published in a leading specialty journal, and it is a meta-analysis pooling many studies. Scored zero for effect reported 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, multi-centre collaboration and free to read, so those were left out: it earned 46 of the 56 points we could judge it on, which is 82 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 9 / 10 | Tier 2 — leading specialty journal (Molecular psychiatry) |
| Journal's citation record | — / 4 | No journal record from OpenAlex — left out of this score |
| 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 | 3 / 5 | 2022 — within 6 year(s) of the newest study here |
| Sample size | 2 / 4 | 140 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 | — / 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 35264725) |
| Free to read | — / 2 | Access not recorded — left out of this score |
| Points | 46 / 56 | Scored on 10 of 20 parts. We have no data for the rest, so they are left out: 46 of the 56 points we could judge it on is 82 out of 100. |
| Total | 82 / 100 | — |
What each of these 20 components measures, and what this score is not →
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Cite this study APA, Vancouver, BibTeX · download .bib or .ris
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APA 7th
Shigemizu, D., Asanomi, Y., Akiyama, S., Mitsumori, R., Niida, S., & Ozaki, K. (2022). Whole-genome sequencing reveals novel ethnicity-specific rare variants associated with Alzheimer's disease. Molecular psychiatry. https://doi.org/10.1038/s41380-022-01483-0
Vancouver
Shigemizu D, Asanomi Y, Akiyama S, Mitsumori R, Niida S, Ozaki K. Whole-genome sequencing reveals novel ethnicity-specific rare variants associated with Alzheimer's disease. Molecular psychiatry. 2022. doi:10.1038/s41380-022-01483-0. PMID: 35264725.
BibTeX
@article{shigemizu2022-35264725,
author = {Shigemizu, Daichi and Asanomi, Yuya and Akiyama, Shintaro and Mitsumori, Risa and Niida, Shumpei and Ozaki, Kouichi},
title = {{Whole-genome sequencing reveals novel ethnicity-specific rare variants associated with Alzheimer's disease}},
journal = {Molecular psychiatry},
year = {2022},
doi = {10.1038/s41380-022-01483-0},
pmid = {35264725},
url = {https://doi.org/10.1038/s41380-022-01483-0}
}
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