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Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease
Sims R, van der Lee SJ, Naj AC, Bellenguez C, Badarinarayan N, Jakobsdottir J, Kunkle BW, Boland A et al.. Nature genetics, 2017-07-17
Topic: Brain proteins, microglia and lab models
We identified rare coding variants associated with Alzheimer's disease in a three-stage case-control study of 85,133 subjects. In stage 1, we genotyped 34,174 samples using a whole-exome microarray. In stage 2, we tested associated variants (P -4 ) in 35,962 independent samples using de novo genotyping and imputed genotypes.
Key findings
- In stage 1, we genotyped 34,174 samples using a whole-exome microarray.
- In stage 2, we tested associated variants (P -4 ) in 35,962 independent samples using de novo genotyping and imputed genotypes.
- In stage 3, we used an additional 14,997 samples to test the most significant stage 2 associations (P -8 ) using imputed genotypes.
- We observed three new genome-wide significant nonsynonymous variants associated with Alzheimer's disease: a protective variant in PLCG2 (rs72824905: p.Pro522Arg, P = 5.38 × 10 -10 , odds ratio (OR) = 0.68, minor allele frequency (MAF) cases = 0.0059, MAF controls = 0.0093), a risk variant in ABI3 (rs616338: p.Ser209Phe, P = 4.56 × 10 -10 , OR = 1.43, MAF cases = 0.011, MAF controls = 0.008), and a new genome-wide significant variant in TREM2 (rs143332484: p.Arg62His, P = 1.55 × 10 -14 , OR = 1.67, MAF cases = 0.0143, MAF controls = 0.0089), a known susceptibility gene for Alzheimer's disease.
Why it matters
In a three-stage genetic study of 85,133 people, the authors found three new protein-changing variants linked to Alzheimer's disease, including "a protective variant in PLCG2" (odds ratio 0.68, rarer in people with Alzheimer's than in controls) and "a risk variant in ABI3". The authors say the findings "implicate microglial-mediated innate immunity", meaning the brain's immune cells. These are rare-variant associations, not causes, and the study tests no treatment or prevention.
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Study details
- Study designcase-control study
- Participants85,133
- Effect sizeOR = 1.43; OR = 1.67
- Evidence strengthModerate
How this study scored 82/100
Published in a leading specialty journal, and it is a case-control study. Scored zero for 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 | 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 | 2017 — within 10 year(s) of the newest study here |
| Sample size | 4 / 4 | 85,133 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 / 7 | Cited 1,019 times (OpenAlex, 2026-10-10) |
| Citations per year | 5 / 5 | 92.6 citations a year over 11 year(s) since 2017 |
| Impact for its field and year | 6 / 6 | Cited 67.0× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 4 / 6 | Cited by 93 other studies in this library |
| Still being cited | 4 / 4 | Cited 256 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 4 / 4 | Last-listed author Florence Pasquier: h-index 101 (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 78 institution(s) in 14 countries |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 28714976) |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Total | 82 / 100 | — |
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Read the original
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Cite this study APA, Vancouver, BibTeX · download .bib or .ris
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.
APA 7th
Sims, R., van der Lee, S. J., Naj, A. C., Bellenguez, C., Badarinarayan, N., Jakobsdottir, J., et al. (2017). Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease. Nature genetics. https://doi.org/10.1038/ng.3916
Vancouver
Sims R, van der Lee SJ, Naj AC, Bellenguez C, Badarinarayan N, Jakobsdottir J, et al. Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease. Nature genetics. 2017. doi:10.1038/ng.3916. PMID: 28714976.
BibTeX
@article{sims2017-28714976,
author = {Sims, R. and van der Lee, S. J. and Naj, A. C. and Bellenguez, C. and Badarinarayan, N. and Jakobsdottir, J. and Kunkle, B. W. and Boland, A. and others},
title = {{Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease}},
journal = {Nature genetics},
year = {2017},
doi = {10.1038/ng.3916},
pmid = {28714976},
url = {https://doi.org/10.1038/ng.3916}
}
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