Single-cell multi-omic profiling of lung immune cells identifies novel asthma risk genes and cell-type specific functions

Single-cell multi-omic profiling of lung immune cells identifies novel asthma risk genes and cell-type specific functions | 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 Research Article Single-cell multi-omic profiling of lung immune cells identifies novel asthma risk genes and cell-type specific functions Jing Gu, Donna C. Decker, Xiaoyuan Zhong, Anne I. Sperling, Carole Ober, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8914109/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 8 You are reading this latest preprint version Abstract Genome-wide studies (GWAS) of asthma have identified nearly 200 genomic loci. However, the underlying mechanisms at most loci remain elusive. While functional profiling of blood immune cell types has helped interpret asthma GWAS signals, high-resolution functional genomic data of lung immune cells, which differ from circulating immune cells, are lacking. We thus performed single-cell multi-omics (RNA-seq and ATAC-seq) in lung and spleen lymphocytes from nine donors. Cross-tissue comparison identified distinct transcriptomes for each immune cell type, but only subtle differences in chromatin accessibility. We next assessed open chromatin regions (OCRs) in lung vs. blood, using a public dataset, for their enrichment of asthma risk. Strikingly, lung T cells showed unique contributions to heritability of adult-onset (AOA) and childhood-onset asthma (COA), beyond blood T cells. Using lung OCRs and previously fine-mapped variants for AOA and COA, we identified 43 cis-regulatory elements (CREs) likely contributing to asthma risk. By creating enhancer-gene maps from our single-cell data, we identified target genes for these CREs. We highlighted CCR4 and LRRC32 with their CREs displaying cell-type specific regulatory activities. Lastly, we built cell-type level gene regulatory networks (GRNs) to identify target genes of transcription factors (TFs). Lung GRNs not only shed light on the cell-type specific functions of several TFs that are known asthma risk genes but also allowed us to detect novel TFs such as STAT1 that may regulate asthma-related biological pathways in CD4 T cells. Our results demonstrate the utility of single-cell multi-omics to identify asthma risk genes and understand their cell-type specific functions. Full Text Additional Declarations No competing interests reported. Supplementary Files Supplemntarytables.zip Cite Share Download PDF Status: Under Review Version 1 posted Reviews received at journal 14 May, 2026 Reviewers agreed at journal 29 Apr, 2026 Reviewers agreed at journal 28 Apr, 2026 Reviewers agreed at journal 21 Mar, 2026 Reviewers invited by journal 19 Mar, 2026 Editor assigned by journal 20 Feb, 2026 Submission checks completed at journal 19 Feb, 2026 First submitted to journal 19 Feb, 2026 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. 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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-8914109","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":610786163,"identity":"dff13515-5a66-4dd7-930e-4eb8e227f5a6","order_by":0,"name":"Jing Gu","email":"","orcid":"","institution":"University of Chicago","correspondingAuthor":false,"prefix":"","firstName":"Jing","middleName":"","lastName":"Gu","suffix":""},{"id":610786164,"identity":"5a5b5ac9-0257-47e9-b763-d5baa9fd59a1","order_by":1,"name":"Donna C. 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