Inflammation is central to Alzheimer's disease (AD) pathogenesis. Microglia, the resident innate immune cells of the brain, exhibit diverse inflammatory states and are enriched for AD-associated genetic variants within active cis-regulatory elements (CREs). However, the interplay among genetic variants, transcription factor (TF)-CRE-gene programs, and microglial responses across inflammatory and disease contexts remain poorly understood. Here, we develop context-dependent epigenomic networks (cEpiNets), integrating bulk and single-nucleus assay for transposase-accessible chromatin using sequencing (ATAC-seq) to reconstruct regulatory programs across inflammatory, genetic perturbation, and disease contexts. Leveraging TF footprinting and graph embedding, cEpiNets identifies shared and context-specific programs and predicts regulatory circuits in unseen biological contexts. In a SORL1-marked inflammatory microglial state that expands during AD progression, cEpiNets annotates AD risk variants at the SORL1 locus and identifies variants associated with cellular state abundance across donors. Cross-context analysis further identifies ZBTB14, whose inflammation-associated program connects AD risk variant-harboring CREs to target genes and widespread TF remodeling in AD. Donor-level ZBTB14 footprint activity is negatively associated with AD pathology, while combined IFN{gamma}/TNF stimulation represses ZBTB14 and activates a subset of inferred targets. Collectively, cEpiNets bridges genetic variation, regulatory programs, and disease-associated cellular phenotypes to facilitate mechanistic interpretation of complex disease genetics.
Fu, T.-T., Kurkela, M., Tu, J., Zhang, J., Sun, N., Farrer, L. A., TCW, J., Hou, L.
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