Integration of cell-specific gene expression and chromatin accessibility facilitates localization of neurodegenerative risk in microglia
Reed X, Acri DJ, Beilina A, Ding J, Saez-Atienzar S, Kaileh M, Bromberek S, Hu F et al.. bioRxiv, 2026-09-17
Topic: Genetics and APOE
Genome-wide association studies (GWAS) have identified many loci that contribute to the risk of neurodegenerative diseases. However, a persistent challenge in interpretation of GWAS is to break loci down to specific genes, variants, and cell types, and thus nominate disease mechanisms. Here, we used iPSC-derived cells containing population-level variation to examine GWAS loci across NDDs including Alzheimer’s disease, Parkinson’s disease and Lewy body dementia. We differentiated a set of 135 iPSC donor lines into two cell types relevant to neurodegeneration, neurons and microglia, and completed single cell gene expression and chromatin accessibility profiling. Meta-analysis of these data with published human brain snRNAseq for QTL mapping identified multiple loci associated with NDDs that are restricted to either neurons or microglia. Colocalization of GWAS and these QTL supports microglia as having a strong contribution to disease risk. We tested peaks nominated at the BIN1 locus for enhancer activity using a perturb-seq-based method in microglia. Our results show one of the nominated peaks controls BIN1 expression in microglia but also modifies expression of other genes at the locus. These results support the hypothesis that common variants affecting gene expression specifically in microglia can contribute directly to NDD risk rather than functioning solely as a secondary response to neurodegeneration. These data also show that iPSC-derived cells are a useful model to experimentally dissect GWAS loci that colocalize with QTL.
Key findings
- Meta-analysis of these data with published human brain snRNAseq for QTL mapping identified multiple loci associated with NDDs that are restricted to either neurons or microglia.
- Our results show one of the nominated peaks controls BIN1 expression in microglia but also modifies expression of other genes at the locus.
- These results support the hypothesis that common variants affecting gene expression specifically in microglia can contribute directly to NDD risk rather than functioning solely as a secondary response to neurodegeneration.
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Study details
- Study designmeta-analysis
- Evidence strengthHigh
How this study scored 16/100
Preprint — not yet peer-reviewed. It scored 47 on the same rubric, but non-peer-reviewed sources are capped at 16, so it shows as 16. Scored zero for sample size, effect reported and studied in people because the record does not state it. We have no data on 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 29 of the 62 points we could judge it on, which is 47 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 2 / 10 | Tier 4 — not a peer-reviewed journal (bioRxiv) |
| Journal's citation record | 0 / 4 | Not a journal article, so the journal's record does not count |
| Study design | 12 / 12 | A meta-analysis pooling many studies |
| Strength of evidence | 5 / 5 | Rated “high” in our summary |
| Peer-review validation | 4 / 10 | Preprint — not yet peer-reviewed. Hosted on a preprint server. |
| How recent | 5 / 5 | 2026 — within 1 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 | 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 | 1 / 2 | Not in PubMed, but has a DOI |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Points | 29 / 62 | Scored on 12 of 20 parts. We have no data for the rest, so they are left out: 29 of the 62 points we could judge it on is 47 out of 100. |
| Total | 47 / 100 | Capped to 16 because this is not a peer-reviewed article. |
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
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
Reed, X., Acri, D. J., Beilina, A., Ding, J., Saez-Atienzar, S., Kaileh, M., et al. (2026). Integration of cell-specific gene expression and chromatin accessibility facilitates localization of neurodegenerative risk in microglia. bioRxiv. https://doi.org/10.64898/2026.09.15.751821
Vancouver
Reed X, Acri DJ, Beilina A, Ding J, Saez-Atienzar S, Kaileh M, et al. Integration of cell-specific gene expression and chromatin accessibility facilitates localization of neurodegenerative risk in microglia. bioRxiv. 2026. doi:10.64898/2026.09.15.751821.
BibTeX
@article{reed2026-9f5b4c53,
author = {Reed, X. and Acri, D. J. and Beilina, A. and Ding, J. and Saez-Atienzar, S. and Kaileh, M. and Bromberek, S. and Hu, F. and others},
title = {{Integration of cell-specific gene expression and chromatin accessibility facilitates localization of neurodegenerative risk in microglia}},
journal = {bioRxiv},
year = {2026},
doi = {10.64898/2026.09.15.751821},
url = {https://doi.org/10.64898/2026.09.15.751821}
}
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