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Exome sequencing identifies rare damaging variants in ATP8B4 and ABCA1 as risk factors for Alzheimer's disease
Holstege H, Hulsman M, Charbonnier C, Grenier-Boley B, Quenez O, Grozeva D, van Rooij JGJ, Sims R et al.. Nature genetics, 2022-11-21
Topic: Amyloid, tau and blood-test diagnosis
Alzheimer's disease (AD), the leading cause of dementia, has an estimated heritability of approximately 70% 1 . The genetic component of AD has been mainly assessed using genome-wide association studies, which do not capture the risk contributed by rare variants 2 . Here, we compared the gene-based burden of rare damaging variants in exome sequencing data from 32,558 individuals-16,036 AD cases and 16,522 controls. Next to variants in TREM2, SORL1 and ABCA7, we observed a significant association of rare, predicted damaging variants in ATP8B4 and ABCA1 with AD risk, and a suggestive signal in ADAM10. Additionally, the rare-variant burden in RIN3, CLU, ZCWPW1 and ACE highlighted these genes as potential drivers of respective AD-genome-wide association study loci. Variants associated with the strongest effect on AD risk, in particular loss-of-function variants, are enriched in early-onset AD cases. Our results provide additional evidence for a major role for amyloid-β precursor protein processing, amyloid-β aggregation, lipid metabolism and microglial function in AD.
Cite this study APA, Vancouver, BibTeX · download .bib or .ris
APA 7th
Holstege, H., Hulsman, M., Charbonnier, C., Grenier-Boley, B., Quenez, O., Grozeva, D., et al. (2022). Exome sequencing identifies rare damaging variants in ATP8B4 and ABCA1 as risk factors for Alzheimer's disease. Nature genetics. https://doi.org/10.1038/s41588-022-01208-7
Vancouver
Holstege H, Hulsman M, Charbonnier C, Grenier-Boley B, Quenez O, Grozeva D, et al. Exome sequencing identifies rare damaging variants in ATP8B4 and ABCA1 as risk factors for Alzheimer's disease. Nature genetics. 2022. doi:10.1038/s41588-022-01208-7. PMID: 36411364.
BibTeX
@article{holstege2022-36411364,
author = {Holstege, H. and Hulsman, M. and Charbonnier, C. and Grenier-Boley, B. and Quenez, O. and Grozeva, D. and van Rooij, J. G. J. and Sims, R. and others},
title = {{Exome sequencing identifies rare damaging variants in ATP8B4 and ABCA1 as risk factors for Alzheimer's disease}},
journal = {Nature genetics},
year = {2022},
doi = {10.1038/s41588-022-01208-7},
pmid = {36411364},
url = {https://doi.org/10.1038/s41588-022-01208-7}
}
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.
Key findings
- Next to variants in TREM2, SORL1 and ABCA7, we observed a significant association of rare, predicted damaging variants in ATP8B4 and ABCA1 with AD risk, and a suggestive signal in ADAM10.
- Variants associated with the strongest effect on AD risk, in particular loss-of-function variants, are enriched in early-onset AD cases.
- Our results provide additional evidence for a major role for amyloid-β precursor protein processing, amyloid-β aggregation, lipid metabolism and microglial function in AD.
Why it matters
By comparing exome sequencing data from over 32,000 people, this study found that rare damaging variants in ATP8B4 and ABCA1 were significantly associated with Alzheimer's disease risk, in addition to variants in TREM2, SORL1 and ABCA7. The results add evidence for roles of amyloid-beta precursor protein processing, amyloid-beta aggregation, lipid metabolism and microglial function in Alzheimer's disease.
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Study details
- Participants32,558
- Evidence strengthLow
How this study scored 68/100
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 (Nature genetics) |
| Journal's citation record | 4 / 4 | Nature Genetics: journal h-index 776 (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 | 3 / 5 | 2022 — within 6 year(s) of the newest study here |
| Sample size | 4 / 4 | 32,558 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 229 times (OpenAlex, 2026-10-10) |
| Citations per year | 4 / 5 | 38.2 citations a year over 6 year(s) since 2022 |
| Impact for its field and year | 5 / 6 | Cited 24.2× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 3 / 6 | Cited by 11 other studies in this library |
| Still being cited | 3 / 4 | Cited 178 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 4 / 4 | Last-listed author John Hardy: h-index 205 (OpenAlex, whole career) |
| Institution's track record | 3 / 3 | University of Washington: institution h-index 3,540 (OpenAlex) |
| Multi-centre collaboration | 3 / 3 | OpenAlex lists 75 institution(s) in 8 countries |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 36411364) |
| Free to read | 2 / 2 | Free to read |
| Total | 68 / 100 | — |
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Read the original
- DOI: 10.1038/s41588-022-01208-7
- PubMed: 36411364
- Original source →
- Free full text: Nature Genetics →
Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).
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