Genetic and Cortical Cell-Type Liability Architecture of Autism

Genetic and Cortical Cell-Type Liability Architecture of Autism | 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 Biological Sciences - Article Genetic and Cortical Cell-Type Liability Architecture of Autism Thomas Renne, Florian Benitière, Cecile Poulain, Alma Dubuc, Vincent Bourque, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8321464/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 Autism Spectrum Disorders (ASD) can result from rare genetic variants interfering with brain development. Whether their effects converge on specific cortical cell types remains unresolved. Previous studies have focused on a narrow set of high-confidence ASD (hcASD) genes, which were enriched in neuronal cell types during prenatal development. By contrast, studies of postnatal cerebral cortex have repeatedly associated ASD with transcriptional changes in both neurons and glia. To comprehensively map ASD genetic liability across cortical cell types, we conducted a functional genetic burden analysis with 124,416 individuals, including ASD probands and unaffected family members. We examined six classes of rare gene-disrupting variants aggregated across a complete spectrum of transcriptomic cell types of the human prefrontal cortex throughout development. We show that cellular liabilities in ASD delineate a broad and developmentally dynamic architecture. Likewise, we uncover high dependency on classes of variants with Loss-of-Function (LoF) and de novo linked to prenatal cells, while duplications, missense, and inherited variants increase liability through postnatal and glial cell types. Notably, inherited LoF variants uncover the contribution of microglia to ASD liability, also supported by transcriptomic evidence from postmortem ASD brains. Finally, we show that overall, variants disrupting genes differentially expressed in postmortem ASD brains significantly contribute to ASD liability, demonstrating convergence between disrupted transcriptomes and genetic liability. Together, our study offers an integrative, cell-type-aware framework for interpreting ASD risk genetics. Biological sciences/Genetics/Neurodevelopmental disorders/Autism spectrum disorders Biological sciences/Genetics/Genetic association study/Genome-wide association studies Biological sciences/Neuroscience/Development of the nervous system/Cell type diversity Biological sciences/Genetics/Functional genomics/Gene expression profiling Biological sciences/Genetics/Sequencing/RNA sequencing Full Text Additional Declarations There is NO Competing Interest. Supplementary Files SupplementaryTables.xlsx Supplementary tables SupplementaryFiguresNature.docx Supplementary data 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. 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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-8321464","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Biological Sciences - Article","associatedPublications":[],"authors":[{"id":584590702,"identity":"a71addcb-2c8d-4558-beea-73b5be24523d","order_by":0,"name":"Thomas 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Whether their effects converge on specific cortical cell types remains unresolved. Previous studies have focused on a narrow set of high-confidence ASD (hcASD) genes, which were enriched in neuronal cell types during prenatal development. By contrast, studies of postnatal cerebral cortex have repeatedly associated ASD with transcriptional changes in both neurons and glia.\u003c/p\u003e \u003cp\u003eTo comprehensively map ASD genetic liability across cortical cell types, we conducted a functional genetic burden analysis with 124,416 individuals, including ASD probands and unaffected family members. We examined six classes of rare gene-disrupting variants aggregated across a complete spectrum of transcriptomic cell types of the human prefrontal cortex throughout development.\u003c/p\u003e \u003cp\u003eWe show that cellular liabilities in ASD delineate a broad and developmentally dynamic architecture. 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