Whole exome sequencing study identifies novel rare and common Alzheimer's-Associated variants involved in immune response and transcriptional regulation
Bis JC, Jian X, Kunkle BW, Chen Y, Hamilton-Nelson KL, Bush WS, Salerno WJ, Lancour D et al.. Molecular psychiatry, 2018-08-14
Topic: Amyloid, tau and blood-test diagnosis
The Alzheimer's Disease Sequencing Project (ADSP) undertook whole exome sequencing in 5,740 late-onset Alzheimer disease (AD) cases and 5,096 cognitively normal controls primarily of European ancestry (EA), among whom 218 cases and 177 controls were Caribbean Hispanic (CH). An age-, sex- and APOE based risk score and family history were used to select cases most likely to harbor novel AD risk variants and controls least likely to develop AD by age 85 years. We tested ~1.5 million single nucleotide variants (SNVs) and 50,000 insertion-deletion polymorphisms (indels) for association to AD, using multiple models considering individual variants as well as gene-based tests aggregating rare, predicted functional, and loss of function variants. Sixteen single variants and 19 genes that met criteria for significant or suggestive associations after multiple-testing correction were evaluated for replication in four independent samples; three with whole exome sequencing (2,778 cases, 7,262 controls) and one with genome-wide genotyping imputed to the Haplotype Reference Consortium panel (9,343 cases, 11,527 controls). The top findings in the discovery sample were also followed-up in the ADSP whole-genome sequenced family-based dataset (197 members of 42 EA families and 501 members of 157 CH families). We identified novel and predicted functional genetic variants in genes previously associated with AD. We also detected associations in three novel genes: IGHG3 (p = 9.8 × 10 -7 ), an immunoglobulin gene whose antibodies interact with β-amyloid, a long non-coding RNA AC099552.4 (p = 1.2 × 10 -7 ), and a zinc-finger protein ZNF655 (gene-based p = 5.0 × 10 -6 ). The latter two suggest an important role for transcriptional regulation in AD pathogenesis.
Key findings
- Sixteen single variants and 19 genes that met criteria for significant or suggestive associations after multiple-testing correction were evaluated for replication in four independent samples; three with whole exome sequencing (2,778 cases, 7,262 controls) and one with genome-wide genotyping imputed to the Haplotype Reference Consortium panel (9,343 cases, 11,527 controls).
- We identified novel and predicted functional genetic variants in genes previously associated with AD.
Why it matters
This large genetic study identified new and predicted functional variants in genes already associated with Alzheimer disease, including genes involved in immune response and transcriptional regulation. It adds to understanding of genetic risk but does not provide a treatment, cure, or prevention.
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Study details
- Evidence strengthLow
How this study scored 45/100
Published in a leading specialty 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, still being cited, senior author's track record, institution's track record and multi-centre collaboration, so those were left out: it earned 29 of the 64 points we could judge it on, which is 45 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 | 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 | 2020 — 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 (OpenAlex dates this DOI to 2018, the record says 2020; OpenAlex values not used) — 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 | 3 / 6 | Cited by 15 other studies in this library |
| 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 30108311) |
| Free to read | 2 / 2 | Free to read |
| Points | 29 / 64 | Scored on 12 of 20 parts. We have no data for the rest, so they are left out: 29 of the 64 points we could judge it on is 45 out of 100. |
| Total | 45 / 100 | — |
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APA 7th
Bis, J. C., Jian, X., Kunkle, B. W., Chen, Y., Hamilton-Nelson, K. L., Bush, W. S., et al. (2020). Whole exome sequencing study identifies novel rare and common Alzheimer's-Associated variants involved in immune response and transcriptional regulation. Molecular psychiatry. https://doi.org/10.1038/s41380-018-0112-7
Vancouver
Bis JC, Jian X, Kunkle BW, Chen Y, Hamilton-Nelson KL, Bush WS, et al. Whole exome sequencing study identifies novel rare and common Alzheimer's-Associated variants involved in immune response and transcriptional regulation. Molecular psychiatry. 2020. doi:10.1038/s41380-018-0112-7. PMID: 30108311.
BibTeX
@article{bis2020-30108311,
author = {Bis, J. C. and Jian, X. and Kunkle, B. W. and Chen, Y. and Hamilton-Nelson, K. L. and Bush, W. S. and Salerno, W. J. and Lancour, D. and others},
title = {{Whole exome sequencing study identifies novel rare and common Alzheimer's-Associated variants involved in immune response and transcriptional regulation}},
journal = {Molecular psychiatry},
year = {2020},
doi = {10.1038/s41380-018-0112-7},
pmid = {30108311},
url = {https://doi.org/10.1038/s41380-018-0112-7}
}
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