Genetic architecture of serum PFAS accumulation and its neurotoxicity in young urban adults

Genetic architecture of serum PFAS accumulation and its neurotoxicity in young urban adults | 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 architecture of serum PFAS accumulation and its neurotoxicity in young urban adults Chunshui Yu, Jiayuan Xu, Xiaojun Xu, Zhihan Yan, Longjiang Zhang, and 49 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8139813/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 Genes impacting the bioaccumulation of perfluoroalkyl and polyfluoroalkyl substances (PFASs) and their neurotoxic effects on the brain and behavior remain unclear. Here, we examined genome-wide associations with serum accumulation of 13 PFASs in 6,823 Chinese urban adults. We revealed that perfluoroheptanoic acid (PFHpA) accumulation was associated with genetic variants at two loci (3q29: P = 5.20 × 10-19; 6p22.2: P = 3.69 × 10-23), mapping to 56 genes. Blood expression of 27 of these genes was associated with PFHpA accumulation in 573 subsamples. Eight genes showed potential causal effects on PFHpA accumulation, functionally linked to innate immunity (TRIM38, ZDHHC19, MUC20) and organic solute transport (SLC51A and SLC17A3). We assessed the impact of PFASs on cortical thickness and surface area, white matter fractional anisotropy and mean diffusivity, along with 25 behavioral phenotypes. We identified that seven PFASs were correlated with reduced cortical morphology, primarily in the prefrontal cortex. We also found a statistical causal effect of PFHpA accumulation on the surface area in the right frontomarginal cortex, which mediated the effect of PFHpA on anxiety. These findings indicate that serum PFHpA accumulation may be regulated by genes related to innate immunity and solute transport, heightening anxiety by impairing the prefrontal cortex. Biological sciences/Neuroscience Social science/Environmental studies Biological sciences/Psychology/Human behaviour perfluoroalkyl and polyfluoroalkyl substances genome-wide association study gene expression neuroimaging behavior causality Full Text Additional Declarations There is NO Competing Interest. Supplementary Files FigureS1.pdf Supplementary figure 1 FigureS2.pdf Supplementary figure 2 FigureS3.pdf Supplementary figure 3 FigureS4.pdf Supplementary figure 4 FigureS5.pdf Supplementary figure 5 FigureS6.pdf Supplementary figure 6 FigureS7.pdf Supplementary figure 7 FigureS8.pdf Supplementary figure 8 FigureS9.pdf Supplementary figure 9 3.20251007xujiayuanPFHpAsupplementarytables.xlsx Supplementary tables 2.20251007xujiayuanPFHpAsupplementaryinformation.pdf Supplementary information 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-8139813","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":581065813,"identity":"602482d7-ba1c-48c7-bc1d-6451a45b3fcb","order_by":0,"name":"Chunshui 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adults","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":"perfluoroalkyl and polyfluoroalkyl substances, genome-wide association study, gene expression, neuroimaging, behavior, causality","lastPublishedDoi":"10.21203/rs.3.rs-8139813/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8139813/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Genes impacting the bioaccumulation of perfluoroalkyl and polyfluoroalkyl substances (PFASs) and their neurotoxic effects on the brain and behavior remain unclear. Here, we examined genome-wide associations with serum accumulation of 13 PFASs in 6,823 Chinese urban adults. We revealed that perfluoroheptanoic acid (PFHpA) accumulation was associated with genetic variants at two loci (3q29: P = 5.20 × 10-19; 6p22.2: P = 3.69 × 10-23), mapping to 56 genes. Blood expression of 27 of these genes was associated with PFHpA accumulation in 573 subsamples. Eight genes showed potential causal effects on PFHpA accumulation, functionally linked to innate immunity (TRIM38, ZDHHC19, MUC20) and organic solute transport (SLC51A and SLC17A3). We assessed the impact of PFASs on cortical thickness and surface area, white matter fractional anisotropy and mean diffusivity, along with 25 behavioral phenotypes. We identified that seven PFASs were correlated with reduced cortical morphology, primarily in the prefrontal cortex. We also found a statistical causal effect of PFHpA accumulation on the surface area in the right frontomarginal cortex, which mediated the effect of PFHpA on anxiety. These findings indicate that serum PFHpA accumulation may be regulated by genes related to innate immunity and solute transport, heightening anxiety by impairing the prefrontal cortex.","manuscriptTitle":"Genetic architecture of serum PFAS accumulation and its neurotoxicity in young urban adults","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-02-10 11:52:08","doi":"10.21203/rs.3.rs-8139813/v1","editorialEvents":[],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"nature-health","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"nathealth","sideBox":"Learn more about [Nature Health](https://www.nature.com/naturehealth/)","snPcode":"44360","submissionUrl":"https://mts-nathealth.nature.com","title":"Nature Health","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"11ff3e29-8076-408f-972a-ba16b8a6459d","owner":[],"postedDate":"February 10th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":61811802,"name":"Biological sciences/Neuroscience"},{"id":61811803,"name":"Social science/Environmental studies"},{"id":61811804,"name":"Biological sciences/Psychology/Human behaviour"}],"tags":[],"updatedAt":"2026-02-10T11:52:08+00:00","versionOfRecord":[],"versionCreatedAt":"2026-02-10 11:52:08","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8139813","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8139813","identity":"rs-8139813","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}