Single-Nucleus Multi-Omic Atlas Maps Regulatory Architecture and Non-Coding Variant Effects across Adult Human Tissues.

Diverse human cell types establish specialized functions through lineage- and context-specific regulatory programs. Interpreting non-coding genetic risk requires integrated multi-omic reference maps that directly connect regulatory DNA to cellular expression across human tissues. Here we present a single-nucleus multiomic atlas comprising 459,856 transcriptomic and chromatin accessibility profiles from 21 adult human tissues across four donors, including paired measurements from 160,688 nuclei. We resolve nine cell lineages, 61 broad cell types and 313 subclusters, and identify 1,085,062 candidate cis-regulatory elements (cCREs), including 161,270 novel elements absent from ENCODE. Regulatory activity was dominated by cell identity but refined by tissue context. Joint profiling enabled 871,177 cCRE-gene associations and revealed lineage-specific regulatory architectures. Cross-tissue analysis of accessibility further identified lineage-restricted and constitutively inaccessible chromatin domains, the latter showing preferential hypomethylation across human cancers. We leveraged this dataset to train sequence-to-function models to predict chromatin-accessibility effects for 548,656 fine-mapped variants, identifying 18,133 high-effect variants, including 1,120 broadly active variants. Models trained for eight endothelial subtypes further resolve predicted variant effects across vascular beds. Together, this study provides a comprehensive cellular and computational framework for interpreting regulatory sequence, context-dependent gene control, and complex trait genetics across the human body.