Genomic and proteomic signatures highlight diverse pathways between obesity and type-2 diabetes

Genomic and proteomic signatures highlight diverse pathways between obesity and type-2 diabetes | 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 Genomic and proteomic signatures highlight diverse pathways between obesity and type-2 diabetes Åsa Johansson, Pascal Mutie, Torgny Karlsson This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6079296/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 Obesity is a significant risk factor for Type 2 diabetes (T2D), a disease that affects about 10% of the global population. Obesity is also a heterogeneous condition, and the molecular mechanisms linking it to T2D are not yet fully understood. The aim of this study was to elucidate causal pathways between obesity and T2D and to characterize their molecular signatures using an innovative multi-omics approach, thereby highlighting why some, but not all, obese individuals develop T2D. We identified 513 independent obesity-associated SNPs by meta-analysing genome-wide association study data from FinnGen and GIANT (N=699,431). Clustering of Mendelian randomization (MR) estimates, computed using T2D data from DIAGRAM (74,124 cases and 824,006 controls), identified four clusters of SNPs. These clusters, all associated with increased body mass index (BMI), showed differential effects on T2D risk, ranging from harmful to protective. Cluster-specific MR analyses identified 212, out of 2922 protein measurements from the UK Biobank (N=54,219), to be causally affected by any of the clusters. Among these, eight proteins were significantly associated with T2D in downstream MR analyses, representing potential pathways responsible for the heterogeneous link between obesity and T2D. These proteins include, for example, SNAP25, PAM, and FSTL3, suggesting that one of the underlying molecular pathways is tightly linked to insulin synthesis and secretion. Health sciences/Medical research/Genetics research Biological sciences/Computational biology and bioinformatics/Functional clustering Health sciences/Endocrinology/Endocrine system and metabolic diseases/Obesity Biological sciences/Genetics/Genomics/Personalized medicine Biological sciences/Drug discovery/Biomarkers/Predictive markers Full Text Additional Declarations There is NO Competing Interest. Supplementary Files NatMetT2DMRClustSupplementaryMaterials250221.pdf Supplementary Materials NatMedBMIT2DMRCLUSTSUPPLEMENTARYFILES250221.xlsx Supplementary Files 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-6079296","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":422382061,"identity":"e4a32162-0a4a-41b3-9c91-e751abcf0090","order_by":0,"name":"Åsa Johansson","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA+0lEQVRIiWNgGAWjYLACCYYDUFaFBMlazhCrhQGmhbGNCLX8/YcfMFhU3JE35z/+8HHhPAu77Qw8ZhIMf2xwu+lGmgGDxJlnhjtn5Bgbz9wmkbyzAaiFsS0NtzU3GAwYJNsOM264wcMmzQvUYnAApKXhME4d8uePfwBpsd9w/vgzad45UC0Mf/7j1GJwIAdsS+KGAwlm0rwNEnYQLWwHcGoxvJFTcEDizOHkDTeAfuE5JpFg2cxWbJHYloxTi9z54xsfS1QctgU67OFjnpo6e3P25o03Pvyxw+19IDiMHH+JG5iBZAJeDcAI/IDEsTcgoHoUjIJRMApGHgAAY75SfvnVQ9MAAAAASUVORK5CYII=","orcid":"https://orcid.org/0000-0002-2915-4498","institution":"Uppsala University","correspondingAuthor":true,"prefix":"","firstName":"Åsa","middleName":"","lastName":"Johansson","suffix":""},{"id":422382062,"identity":"7a32c944-a9af-4127-9b3a-5a18c820dbb9","order_by":1,"name":"Pascal Mutie","email":"","orcid":"https://orcid.org/0000-0003-2626-1703","institution":"Uppsala University","correspondingAuthor":false,"prefix":"","firstName":"Pascal","middleName":"","lastName":"Mutie","suffix":""},{"id":422382063,"identity":"05fb7b55-beed-4b14-a144-39443eebd63b","order_by":2,"name":"Torgny Karlsson","email":"","orcid":"https://orcid.org/0000-0001-8095-6149","institution":"Uppsala University","correspondingAuthor":false,"prefix":"","firstName":"Torgny","middleName":"","lastName":"Karlsson","suffix":""}],"badges":[],"createdAt":"2025-02-21 12:01:33","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6079296/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6079296/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":78492987,"identity":"c2eb11d0-81ef-442a-a142-f1dd98e1e3b1","added_by":"auto","created_at":"2025-03-14 03:13:31","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1350571,"visible":true,"origin":"","legend":"Article File","description":"","filename":"NatMetManuscriptT2Dmrclust250221.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6079296/v1_covered_cd44681f-cc4e-460b-85bb-9a7fadd31d3d.pdf"},{"id":78492504,"identity":"a5b73c86-2221-4195-a75a-015a86cde150","added_by":"auto","created_at":"2025-03-14 03:05:29","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":325875,"visible":true,"origin":"","legend":"Supplementary Materials","description":"","filename":"NatMetT2DMRClustSupplementaryMaterials250221.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6079296/v1/6108b47a16d8de5c0f0b6067.pdf"},{"id":78492507,"identity":"3bbc004d-dd89-40e1-9190-b53360456b11","added_by":"auto","created_at":"2025-03-14 03:05:29","extension":"xlsx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":3383313,"visible":true,"origin":"","legend":"Supplementary Files","description":"","filename":"NatMedBMIT2DMRCLUSTSUPPLEMENTARYFILES250221.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-6079296/v1/e24636a7f5a7dbc5174da441.xlsx"}],"financialInterests":"There is \u003cb\u003eNO\u003c/b\u003e Competing Interest.","formattedTitle":"Genomic and proteomic signatures highlight diverse pathways between obesity and type-2 diabetes","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"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-6079296/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6079296/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Obesity is a significant risk factor for Type 2 diabetes (T2D), a disease that affects about 10% of the global population. 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