Genetic mechanisms underlying the associations between brain structure and mental health

Genetic mechanisms underlying the associations between brain structure and mental health | 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 Genetic mechanisms underlying the associations between brain structure and mental health Bing Liu, Ke Hu, Xiaohan Tian, Jing Lou, Chaoyue Ding, Tingting Zhang, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7996571/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 Brain-wide association studies (BWAS) have linked brain structure to complex mental health phenotypes, yet the genetic underpinnings of these BWAS effects remain unknown. Leveraging multimodal neuroimaging, behavioral and genetic data from UK Biobank, we developed an integrative framework combining BWAS and genome-wide association studies (GWAS) to elucidate how genetic variants affect the relationship between brain structure and mental health. Our multivariate BWAS identified two reproducible brain structural modes: a cerebellar-dominant mode and a cortical-dominant mode that explain individual differences in mental health measures. Subsequent GWAS identified 30 and 15 independent significant variants for the two modes, respectively, indicating distinct genetic architectures with no signal overlap. Post-GWAS analyses further revealed distinct biological pathways: genes related to the cerebellar-dominant mode was enriched for gene sets involved in chromatin organization and epigenetic regulation, whereas the cortical-dominant mode was linked to neurotransmitter metabolism. Moreover, we identified shared genetic influences between the brain modes and both mental health and cognitive traits, as well as causal effects of the brain modes on these outcomes. Collectively, our study illuminate how genetic variants contributes to psychological vulnerability through specific neuroanatomical patterns, providing a unified framework for interpreting BWAS in a genetic context. Biological sciences/Neuroscience/Neurogenesis Health sciences/Diseases/Psychiatric disorders Biological sciences/Genetics/Genetic association study/Genome-wide association studies Full Text Additional Declarations There is NO Competing Interest. Supplementary Files SupplementarytableS2.xlsx Supplementary table S2 SupplementarytableS5.xlsx Supplementary table S5 SupplementarytableS1.xlsx Supplementary table S1 SupplementarytableS6.xlsx Supplementary table S6 SupplementarytableS3.xlsx Supplementary table S3 SupplementarytableS4.xlsx Supplementary table S4 Supplementaryfigures.docx Supplementary figures 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. 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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-7996571","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":544010488,"identity":"2e8dee1d-6dd0-4600-99aa-3cc502259e33","order_by":0,"name":"Bing 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