Single-Nucleus Atlas of Cell-Type Specific Genetic Regulation in the Human Brain

Single-Nucleus Atlas of Cell-Type Specific Genetic Regulation in the Human Brain | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Biological Sciences - Article Single-Nucleus Atlas of Cell-Type Specific Genetic Regulation in the Human Brain Gabriel Hoffman, Biao Zeng, Hui Yang, Prashant N.M., Sanan Venkatesh, and 11 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5368620/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted You are reading this latest preprint version Abstract Genetic risk variants for common diseases are predominantly located in non-coding regulatory regions and modulate gene expression. Although bulk tissue studies have elucidated shared mechanisms of regulatory and disease-associated genetics, the cellular specificity of these mechanisms remains largely unexplored. This study presents a comprehensive single-nucleus multi-ancestry atlas of genetic regulation of gene expression in the human prefrontal cortex, comprising 5.6 million 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 857 showing cell type-specific regulatory effects at the class level and 981 at the subclass level. Colocalization of genetic variants associated with gene regulation and disease traits uncovers novel cell type-specific genes implicated in Alzheimer's disease, schizophrenia, and other disorders, which 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 trans-regulatory effects, revealing distal regulation of gene expression. This high-resolution atlas provides unprecedented 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. Biological sciences/Genetics/Gene regulation Biological sciences/Neuroscience Full Text Additional Declarations There is NO Competing Interest. Supplementary Files PsychADSupplement.pdf Supplementary Figures Cite Share Download PDF Status: Under Review Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5368620","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Biological Sciences - Article","associatedPublications":[],"authors":[{"id":372739267,"identity":"a960c0ea-02b6-4898-801c-3a550538ca4d","order_by":0,"name":"Gabriel 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