A Modality-Aware CRISPR Actionability Framework for Functional Prioritization of Genome-Wide Significant Type 2 Diabetes Loci

A Modality-Aware CRISPR Actionability Framework for Functional Prioritization of Genome-Wide Significant Type 2 Diabetes Loci | 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 A Modality-Aware CRISPR Actionability Framework for Functional Prioritization of Genome-Wide Significant Type 2 Diabetes Loci Mohd Mehboob Uddin, Syed Mohd Zakariya Ali Khan This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8957202/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Genome-wide association studies (GWAS) have identified numerous loci associated with Type 2 Diabetes (T2D), yet translating statistical signals into experimentally testable hypotheses remains a central challenge in post-GWAS biology. The predominance of non-coding regulatory variants complicates target gene assignment and raises uncertainty regarding optimal CRISPR perturbation strategy. Here, we present a structured CRISPR Actionability Framework that integrates genomic context, pancreatic islet enhancer overlap, tissue-specific expression validation, and locus clarity into a quantitative CRISPR Actionability Score (CAS). We applied this framework to ten genome-wide significant T2D loci and assigned modality-aware CRISPR strategies (knockout versus CRISPR interference). CAS values ranged from 4 to 10, enabling tiered prioritization into high, moderate, and lower experimental priority classes. High-priority loci included SLC30A8, TCF7L2, and KCNJ11, which demonstrated strong regulatory or coding evidence combined with islet expression support. By explicitly linking genomic architecture to perturbation modality, this framework provides a transparent and reproducible bridge between statistical genetics and functional genome editing. This approach establishes a scalable template for rational CRISPR target selection in complex disease research. Type 2 Diabetes GWAS CRISPR Functional Genomics Enhancer Regulation Genome Editing. Full Text Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted 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-8957202","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":602636985,"identity":"b53ed36e-923b-4144-a1d4-d586b23bf594","order_by":0,"name":"Mohd Mehboob Uddin","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA2UlEQVRIiWNgGAWjYHACNmYgkQBEBgcYKoBMZuYGUrScAWlhJEELA2MbSICAFt1ph489LqiwyTM4nrzxcOG82mj+dqCWHxXbcGoxu52WbjzjTFqxwZlnBYdnbjueO+MwYwNjz5nbeLTkmEnzth1O3HAjx+Aw77ZjuQ1ALcyMbfi05H9D0jLnWO58wlpy2JC0NNTkbiCsJc1MGuQXSZBfeI4dyN0I1HIQv1+Sn0mDQozvePLmzzw1dbnzzh8++OBHBW4t6OAwmDxAtHogqCNF8SgYBaNgFIwQAABGKWO0dtHqjgAAAABJRU5ErkJggg==","orcid":"","institution":"Osmania University","correspondingAuthor":true,"prefix":"","firstName":"Mohd","middleName":"Mehboob","lastName":"Uddin","suffix":""},{"id":602636989,"identity":"d66d885b-f95d-4514-9936-dfd3b8aeffb8","order_by":1,"name":"Syed Mohd Zakariya Ali Khan","email":"","orcid":"","institution":"Osmania University","correspondingAuthor":false,"prefix":"","firstName":"Syed","middleName":"Mohd Zakariya Ali","lastName":"Khan","suffix":""}],"badges":[],"createdAt":"2026-02-24 12:09:04","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8957202/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8957202/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":104405379,"identity":"50100448-46d0-4121-81e6-f76d5ae9a062","added_by":"auto","created_at":"2026-03-11 12:22:44","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":862191,"visible":true,"origin":"","legend":"","description":"","filename":"MGGFINALCRISPR21.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8957202/v1_covered_ce16f719-ef3d-4782-828e-260afcf14e26.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"A Modality-Aware CRISPR Actionability Framework for Functional Prioritization of Genome-Wide Significant Type 2 Diabetes Loci","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"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":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Type 2 Diabetes, GWAS, CRISPR, Functional Genomics, Enhancer Regulation, Genome Editing.","lastPublishedDoi":"10.21203/rs.3.rs-8957202/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8957202/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eGenome-wide association studies (GWAS) have identified numerous loci associated with Type 2 Diabetes (T2D), yet translating statistical signals into experimentally testable hypotheses remains a central challenge in post-GWAS biology. The predominance of non-coding regulatory variants complicates target gene assignment and raises uncertainty regarding optimal CRISPR perturbation strategy. Here, we present a structured CRISPR Actionability Framework that integrates genomic context, pancreatic islet enhancer overlap, tissue-specific expression validation, and locus clarity into a quantitative CRISPR Actionability Score (CAS). We applied this framework to ten genome-wide significant T2D loci and assigned modality-aware CRISPR strategies (knockout versus CRISPR interference). CAS values ranged from 4 to 10, enabling tiered prioritization into high, moderate, and lower experimental priority classes. High-priority loci included SLC30A8, TCF7L2, and KCNJ11, which demonstrated strong regulatory or coding evidence combined with islet expression support. By explicitly linking genomic architecture to perturbation modality, this framework provides a transparent and reproducible bridge between statistical genetics and functional genome editing. This approach establishes a scalable template for rational CRISPR target selection in complex disease research.\u003c/p\u003e","manuscriptTitle":"A Modality-Aware CRISPR Actionability Framework for Functional Prioritization of Genome-Wide Significant Type 2 Diabetes Loci","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-03-09 15:15:30","doi":"10.21203/rs.3.rs-8957202/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"db3415c0-4ca0-4d86-b866-86bc49f5ec65","owner":[],"postedDate":"March 9th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-05-01T02:24:18+00:00","versionOfRecord":[],"versionCreatedAt":"2026-03-09 15:15:30","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8957202","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8957202","identity":"rs-8957202","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}