Integration of cell-specific gene expression and chromatin accessibility facilitates localization of neurodegenerative risk in microglia
- 1National Institute on Aging
Abstract
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.
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BibTeX
@misc{reed2026integration,
title = {{Integration of cell-specific gene expression and chromatin accessibility facilitates localization of neurodegenerative risk in microglia}},
author = {X. Reed and D. J. Acri and A. Beilina and J. Ding and S. Saez-Atienzar and M. Kaileh and S. Bromberek and F. Hu and G. Lerner and D. M. Ramos and S. Solaiman and M. Portley and C. A. Weller and D. T. Whitaker and D. J. Ehrlich and L. Ferrucci and S. W. Scholz and J. R. Gibbs and M. R. Cookson},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.15.751821},
url = {https://www.biorxiv.org/content/10.64898/2026.09.15.751821v1},
note = {CC0},
}
RIS
TY - UNPB
TI - Integration of cell-specific gene expression and chromatin accessibility facilitates localization of neurodegenerative risk in microglia
AU - X. Reed
AU - D. J. Acri
AU - A. Beilina
AU - J. Ding
AU - S. Saez-Atienzar
AU - M. Kaileh
AU - S. Bromberek
AU - F. Hu
AU - G. Lerner
AU - D. M. Ramos
AU - S. Solaiman
AU - M. Portley
AU - C. A. Weller
AU - D. T. Whitaker
AU - D. J. Ehrlich
AU - L. Ferrucci
AU - S. W. Scholz
AU - J. R. Gibbs
AU - M. R. Cookson
PY - 2026
DA - 2026/09/15
PB - bioRxiv
DO - 10.64898/2026.09.15.751821
UR - https://www.biorxiv.org/content/10.64898/2026.09.15.751821v1
AB - 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.
ER -