A novel in silico transcription factor perturbation simulator uncovers diverse genetic architecture of brain disorders

A novel in silico transcription factor perturbation simulator uncovers diverse genetic architecture of brain disorders | 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 Method Article A novel in silico transcription factor perturbation simulator uncovers diverse genetic architecture of brain disorders Haiyang Wang, Qingyu Li, Ying Zhu This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5290734/v1 This work is licensed under a CC BY 4.0 License Status: Under Revision Version 1 posted 11 You are reading this latest preprint version Abstract Brain disorders with complex genetic architectures pose challenges in studying their mechanisms and developing treatments. As experimental approaches fall short due to these complexities, we developed TFdisc, a novel in silico transcription factor (TF) perturbation simulator that uses wild-type single-cell RNA sequencing (scRNA-seq) data to emulate corresponding scRNA-seq transcriptomes post-TF perturbations. Validation confirms TFdisc’s accuracy in reconstructing gene regulatory networks, identifying differentially expressed genes, and predicting alterations in cell identity and lineage differentiation post-TF perturbations. Applying TFdisc to simulate perturbations of individual risk TFs associated with brain disorders reveals distinct molecular and cellular mechanisms. Further simulation of multiple TF simultaneous perturbations uncovered previously uncharacterized genetic architectures for SCZ and ASD, proposing a “jigsaw mechanism” for SCZ and a “monolithic mechanism” for ASD. Further analysis of ASD risk TFs identified clusters whose perturbation leads to differential expression of genes related to synaptic function, cognition, learning, and histone modifications, with varying impacts correlated with autism severity. Full Text Additional Declarations No competing interests reported. Supplementary Files SupplementaryNotes.pdf SupplementaryTables.zip Cite Share Download PDF Status: Under Revision Version 1 posted Editorial decision: Revision requested 19 Jun, 2025 Reviews received at journal 03 Jun, 2025 Reviews received at journal 24 Apr, 2025 Reviewers agreed at journal 24 Apr, 2025 Reviewers agreed at journal 20 Mar, 2025 Reviewers agreed at journal 17 Feb, 2025 Reviewers invited by journal 24 Nov, 2024 Editor assigned by journal 28 Oct, 2024 Editor invited by journal 28 Oct, 2024 Submission checks completed at journal 21 Oct, 2024 First submitted to journal 18 Oct, 2024 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-5290734","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Method Article","associatedPublications":[],"authors":[{"id":371373315,"identity":"35beae5d-e3b0-4328-ae32-da414d50aac2","order_by":0,"name":"Haiyang Wang","email":"","orcid":"","institution":"Fudan University","correspondingAuthor":false,"prefix":"","firstName":"Haiyang","middleName":"","lastName":"Wang","suffix":""},{"id":371373317,"identity":"3e6473dc-8c88-4909-831f-6029c967cdeb","order_by":1,"name":"Qingyu Li","email":"","orcid":"","institution":"Fudan University","correspondingAuthor":false,"prefix":"","firstName":"Qingyu","middleName":"","lastName":"Li","suffix":""},{"id":371373318,"identity":"e417b982-f6f0-4a52-8171-8efa71425bcc","order_by":2,"name":"Ying Zhu","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA7UlEQVRIiWNgGAWjYDACZjB5gIGf+QCDBJRNpBbJtgRitTBAlRkcI1aLwXHewy8Y/txJ3HyMx/DGzx0Mcnw3Ehg/F+DTcpgvzYKB51nitmM8xpa9ZxiMJW8kMEvPwKuFx8yAQeJw4rb7PWYSvG0MiRtuJLAx8xDUYnA4cXMbj5nk3zaGemK0GD9gSDicuIGNx0waaEuCASEtkkBbgIF02HjGMbZia9k2CcOZZx42S+PTwnf+jPEHhj+HZfvbmDfefNtmI893PPngZ3xaFA4wsEn/QfBBUcPYgEcDA4N8AwPzB7wqRsEoGAWjYBQAAF0hTL5Lb1gBAAAAAElFTkSuQmCC","orcid":"","institution":"Fudan University","correspondingAuthor":true,"prefix":"","firstName":"Ying","middleName":"","lastName":"Zhu","suffix":""}],"badges":[],"createdAt":"2024-10-18 16:23:10","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5290734/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5290734/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":67959120,"identity":"f14a3a23-16be-4208-bd09-6e5daf6c749f","added_by":"auto","created_at":"2024-10-31 17:11:23","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":5171401,"visible":true,"origin":"","legend":"","description":"","filename":"Manuscripts.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5290734/v1_covered_ffb54b47-d64b-47e0-a187-81e14a5da204.pdf"},{"id":67958457,"identity":"b313e6df-e025-4a9c-a72b-683517dd781b","added_by":"auto","created_at":"2024-10-31 17:03:13","extension":"pdf","order_by":7,"title":"","display":"","copyAsset":false,"role":"supplement","size":227778,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryNotes.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5290734/v1/9eb2d6d431e66d6400d09522.pdf"},{"id":67958458,"identity":"53b81589-b1bc-40c4-88f4-030ba9c13bb6","added_by":"auto","created_at":"2024-10-31 17:03:14","extension":"zip","order_by":8,"title":"","display":"","copyAsset":false,"role":"supplement","size":12213277,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryTables.zip","url":"https://assets-eu.researchsquare.com/files/rs-5290734/v1/298f4ac4764d67374c377143.zip"}],"financialInterests":"No competing interests reported.","formattedTitle":"A novel in silico transcription factor perturbation simulator uncovers diverse genetic architecture of brain disorders","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"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":"genome-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"Learn more about [Genome Medicine](https://genomemedicine.biomedcentral.com/)","snPcode":"13073","submissionUrl":"https://submission.springernature.com/new-submission/13073/3","title":"Genome Medicine","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-5290734/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5290734/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Brain disorders with complex genetic architectures pose challenges in studying their mechanisms and developing treatments. 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