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Although bulk tissue studies have elucidated shared mechanisms of regulatory and disease-associated genetics, the cellular specificity of these mechanisms remains largely unexplored. Here we present a comprehensive, single-nucleus multi-ancestry atlas of genetic regulation of gene expression in the human prefrontal cortex, comprising 5.6\u2009million nuclei from 1,384 donors of diverse ancestries. Through multi-resolution analyses spanning eight major cell classes and 27 subclasses, we identify genetic regulation for 14,258 genes, with 981 showing cell type-specific regulatory effects at the class level and 857 at the subclass level. Colocalization of genetic variants associated with gene regulation and disease traits uncovers novel cell type-specific genes implicated in Alzheimer\u2019s disease, schizophrenia and other disorders that were not detectable in bulk tissue analyses. Analysis of dynamic genetic regulation at the single-nucleus level identifies 2,073 genes with regulatory effects that vary across developmental trajectories, inferred from a broad age range of donors. We also uncover 1,655 genes with\n                    <jats:italic>trans<\/jats:italic>\n                    -regulatory effects, revealing distal regulation of gene expression. This high-resolution atlas provides insight into the cell type-specific regulatory architecture of the human brain, and offers novel mechanistic targets for understanding the genetic basis of neuropsychiatric and neurodegenerative diseases.\n                  <\/jats:p>","DOI":"10.1038\/s41588-026-02733-5","type":"journal-article","created":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T15:06:06Z","timestamp":1790175966000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Single-nucleus atlas of cell-type specific genetic regulation in the human brain"],"prefix":"10.1038","author":[{"given":"Biao","family":"Zeng","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3548-5637","authenticated-orcid":false,"given":"Prashant","family":"N. 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