131 genetic loci highlight immunological pathways and tissues in nasal polyposis and asthma

131 genetic loci highlight immunological pathways and tissues in nasal polyposis and asthma | 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 Article 131 genetic loci highlight immunological pathways and tissues in nasal polyposis and asthma Elmo Saarentaus, Kasper Fischer-Rasmussen, Eeva Sliz, Argyro Bizaki-Vallaskangas, and 7 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5001302/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 10 Nov, 2025 Read the published version in Nature Communications → Version 1 posted You are reading this latest preprint version Abstract The coexistence of asthma and chronic rhinosinusitis with nasal polyposis (CRSwNP) is associated with allergic phenotypes, disease severity and failure of first-line treatment for both asthma and CRSwNP. Recent studies have highlighted shared genetic components for these diseases. To better understand this shared component, we performed genome-wide meta-analyses of asthma (n = 71,481), CRSwNP (n = 9626) and chronic rhinosinusitis without nasal polyposis (CRSsNP, n = 15,448) in FinnGen and UKB (685,602 controls). We detected 131 genomic associations, including 17 novel loci for asthma, 33 novel loci for CRSwNP, and one for CRSsNP. A shared impact on asthma and CRSwNP was observed at 71 loci. A cross-trait meta-analysis using all disorders further implicated 17 loci associated with asthma or asthma and CRSwNP. These loci largely cluster into three groups, with a shared risk being the most frequent. We also found 17 nonsynonymous associating variants, including a novel TP63 missense variant linked with CRSwNP (OR = 1.519 [1.331–1.734]). Gene set analyses confirmed enrichment of type 2 inflammation genes, and linked FOXP3 signaling to CRSwNP. Our results highlight new shared and separate genetic pathways for CRSwNP and asthma. These provide several avenues of further investigation in functional and epidemiological follow-up, and evidence for immunological and non-immunological mechanisms behind both diseases. Biological sciences/Genetics/Genetic association study/Genome-wide association studies Health sciences/Diseases/Respiratory tract diseases/Asthma Health sciences/Diseases/Immunological disorders/Inflammatory diseases Full Text Additional Declarations There is NO Competing Interest. Supplementary Files Supplementarynotev1.1.docx Supplemental Note SupplementaryDatav1.1.xlsx Supplemental Data Supplementarynotev1.1.docx Cite Share Download PDF Status: Published Journal Publication published 10 Nov, 2025 Read the published version in Nature Communications → 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-5001302","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":351746078,"identity":"a3e82309-7c36-4f21-af91-c9bd65d50b90","order_by":0,"name":"Elmo Saarentaus","email":"data:image/png;base64,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","orcid":"https://orcid.org/0000-0002-8475-7187","institution":"University of Helsinki","correspondingAuthor":true,"prefix":"","firstName":"Elmo","middleName":"","lastName":"Saarentaus","suffix":""},{"id":351746079,"identity":"cc0ee4be-f1ee-4170-bdad-7360f935ab67","order_by":1,"name":"Kasper Fischer-Rasmussen","email":"","orcid":"https://orcid.org/0009-0002-3191-1862","institution":"University of Copenhagen","correspondingAuthor":false,"prefix":"","firstName":"Kasper","middleName":"","lastName":"Fischer-Rasmussen","suffix":""},{"id":351746080,"identity":"9609e432-d8fd-477d-82fa-2efb869ea494","order_by":2,"name":"Eeva Sliz","email":"","orcid":"https://orcid.org/0000-0002-2316-058X","institution":"University of Oulu","correspondingAuthor":false,"prefix":"","firstName":"Eeva","middleName":"","lastName":"Sliz","suffix":""},{"id":351746081,"identity":"0e89fd64-5106-414e-b9c7-38d900f04de4","order_by":3,"name":"Argyro Bizaki-Vallaskangas","email":"","orcid":"","institution":"University of Tampere","correspondingAuthor":false,"prefix":"","firstName":"Argyro","middleName":"","lastName":"Bizaki-Vallaskangas","suffix":""},{"id":351746082,"identity":"878e11b6-291b-4e76-9e48-d95028091846","order_by":4,"name":"Tarja Laitinen","email":"","orcid":"","institution":"University of Helsinki","correspondingAuthor":false,"prefix":"","firstName":"Tarja","middleName":"","lastName":"Laitinen","suffix":""},{"id":351746083,"identity":"f7142080-5d8c-4c13-b5e1-c440b6132a00","order_by":5,"name":"Sanna Toppila-salmi","email":"","orcid":"","institution":"University of Helsinki","correspondingAuthor":false,"prefix":"","firstName":"Sanna","middleName":"","lastName":"Toppila-salmi","suffix":""},{"id":351746084,"identity":"9958706c-0aa6-4cea-af06-e77390402a19","order_by":6,"name":"Hannu Kankaanranta","email":"","orcid":"","institution":"University of Tampere","correspondingAuthor":false,"prefix":"","firstName":"Hannu","middleName":"","lastName":"Kankaanranta","suffix":""},{"id":351746085,"identity":"80e9ff71-09d2-462b-96d6-53143ff2c8fc","order_by":7,"name":"Johannes Kettunen","email":"","orcid":"https://orcid.org/0000-0002-3345-491X","institution":"University of Oulu","correspondingAuthor":false,"prefix":"","firstName":"Johannes","middleName":"","lastName":"Kettunen","suffix":""},{"id":351746086,"identity":"abf6b72c-c776-4340-9b4a-9e578d51d30b","order_by":8,"name":"Klaus Bønnelykke","email":"","orcid":"https://orcid.org/0000-0003-2003-1018","institution":"COPSAC, Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark","correspondingAuthor":false,"prefix":"","firstName":"Klaus","middleName":"","lastName":"Bønnelykke","suffix":""},{"id":351746087,"identity":"b242ead5-c074-4a7e-9a4b-adad83d45ca1","order_by":9,"name":"Aarno Palotie","email":"","orcid":"https://orcid.org/0000-0002-2527-5874","institution":"University of Helsinki","correspondingAuthor":false,"prefix":"","firstName":"Aarno","middleName":"","lastName":"Palotie","suffix":""},{"id":351746088,"identity":"2376685a-66c4-408c-9373-70c5e59854c5","order_by":10,"name":"Antti Mäkitie","email":"","orcid":"","institution":"University of Helsinki","correspondingAuthor":false,"prefix":"","firstName":"Antti","middleName":"","lastName":"Mäkitie","suffix":""}],"badges":[],"createdAt":"2024-08-30 05:30:14","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5001302/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5001302/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s41467-025-64847-4","type":"published","date":"2025-11-10T05:00:00+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":95611253,"identity":"d0d4b4d1-7425-4024-a274-fc5344900a32","added_by":"auto","created_at":"2025-11-11 08:05:42","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":842040,"visible":true,"origin":"","legend":"Article File","description":"","filename":"CRSASTHMAMANUSCRIPTv1.3.3.1.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5001302/v1_covered_ef89def1-7aaf-4e41-a5b5-697e8f0d46ce.pdf"},{"id":64421995,"identity":"4690fea6-f746-4102-8ffb-2ce0bb9897da","added_by":"auto","created_at":"2024-09-13 02:55:40","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":471306,"visible":true,"origin":"","legend":"Supplemental Note","description":"","filename":"Supplementarynotev1.1.docx","url":"https://assets-eu.researchsquare.com/files/rs-5001302/v1/f66ee214e5d14a4e6811ebc6.docx"},{"id":64421994,"identity":"9353b861-64a7-47f0-8ce9-19cd46163d21","added_by":"auto","created_at":"2024-09-13 02:55:40","extension":"xlsx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":178198,"visible":true,"origin":"","legend":"Supplemental Data","description":"","filename":"SupplementaryDatav1.1.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-5001302/v1/6591e55d4ca9c4fd6eb3fa28.xlsx"},{"id":64421996,"identity":"48d92041-198b-4798-83af-0afe00b5698d","added_by":"auto","created_at":"2024-09-13 02:55:40","extension":"docx","order_by":6,"title":"","display":"","copyAsset":false,"role":"supplement","size":471306,"visible":true,"origin":"","legend":"","description":"","filename":"Supplementarynotev1.1.docx","url":"https://assets-eu.researchsquare.com/files/rs-5001302/v1/09729bf7e83a3ae3f6c26a9d.docx"}],"financialInterests":"There is \u003cb\u003eNO\u003c/b\u003e Competing Interest.","formattedTitle":"131 genetic loci highlight immunological pathways and tissues in nasal polyposis and asthma","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"nature-portfolio","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"","title":"Nature Portfolio","twitterHandle":"","acdcEnabled":false,"dfaEnabled":false,"editorialSystem":"ejp","reportingPortfolio":"","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-5001302/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5001302/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"The coexistence of asthma and chronic rhinosinusitis with nasal polyposis (CRSwNP) is associated with allergic phenotypes, disease severity and failure of first-line treatment for both asthma and CRSwNP. Recent studies have highlighted shared genetic components for these diseases. \r\nTo better understand this shared component, we performed genome-wide meta-analyses of asthma (n = 71,481), CRSwNP (n = 9626) and chronic rhinosinusitis without nasal polyposis (CRSsNP, n = 15,448) in FinnGen and UKB (685,602 controls). \r\nWe detected 131 genomic associations, including 17 novel loci for asthma, 33 novel loci for CRSwNP, and one for CRSsNP. A shared impact on asthma and CRSwNP was observed at 71 loci. A cross-trait meta-analysis using all disorders further implicated 17 loci associated with asthma or asthma and CRSwNP. These loci largely cluster into three groups, with a shared risk being the most frequent. We also found 17 nonsynonymous associating variants, including a novel TP63 missense variant linked with CRSwNP (OR = 1.519 [1.331–1.734]). Gene set analyses confirmed enrichment of type 2 inflammation genes, and linked FOXP3 signaling to CRSwNP. \r\nOur results highlight new shared and separate genetic pathways for CRSwNP and asthma. These provide several avenues of further investigation in functional and epidemiological follow-up, and evidence for immunological and non-immunological mechanisms behind both diseases.","manuscriptTitle":"131 genetic loci highlight immunological pathways and tissues in nasal polyposis and asthma","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-09-13 02:55:35","doi":"10.21203/rs.3.rs-5001302/v1","editorialEvents":[],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"nature-communications","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"NCOMMS","sideBox":"Learn more about [Nature Communications](http://www.nature.com/ncomms/)","snPcode":"","submissionUrl":"https://mts-ncomms.nature.com/","title":"Nature Communications","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature Communications","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"bd294545-a9b4-4898-9f47-8be18e493a60","owner":[],"postedDate":"September 13th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":37353326,"name":"Biological sciences/Genetics/Genetic association study/Genome-wide association studies"},{"id":37353327,"name":"Health sciences/Diseases/Respiratory tract diseases/Asthma"},{"id":37353328,"name":"Health sciences/Diseases/Immunological disorders/Inflammatory diseases"}],"tags":[],"updatedAt":"2025-11-11T08:05:30+00:00","versionOfRecord":{"articleIdentity":"rs-5001302","link":"https://doi.org/10.1038/s41467-025-64847-4","journal":{"identity":"nature-communications","isVorOnly":false,"title":"Nature Communications"},"publishedOn":"2025-11-10 05:00:00","publishedOnDateReadable":"November 10th, 2025"},"versionCreatedAt":"2024-09-13 02:55:35","video":"","vorDoi":"10.1038/s41467-025-64847-4","vorDoiUrl":"https://doi.org/10.1038/s41467-025-64847-4","workflowStages":[]},"version":"v1","identity":"rs-5001302","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5001302","identity":"rs-5001302","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}