Integration of cell-specific gene expression and chromatin accessibility facilitates localization of neurodegenerative risk in microglia.
Integration of cell-specific gene expression and chromatin accessibility facilitates localization of neurodegenerative risk in microglia.
Where did the research take place?
The study site has not been established. Author addresses may differ from where the research occurred.
Bethesda, US · Author affiliation
Cell Biology and Gene Expression Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.Location evidence
US · Author affiliation · country only
Department of Neurology, The Ohio State University Wexner Medical Center, Columbus, 43210, Ohio, USA.Location evidence
Baltimore, US · Author affiliation
Laboratory of Molecular Biology and Immunology, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA.Location evidence
Hopkins, US · Author affiliation
Department of Neurology, Johns Hopkins University Medical Center, Baltimore, MD, USA.Location evidence
Publication status: preprint
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Original 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.