Multi-ancestry genome-wide association study of severe pregnancy nausea and vomiting identifies risk loci associated with appetite, insulin signaling, and brain plasticity

Multi-ancestry genome-wide association study of severe pregnancy nausea and vomiting identifies risk loci associated with appetite, insulin signaling, and brain plasticity | 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 Multi-ancestry genome-wide association study of severe pregnancy nausea and vomiting identifies risk loci associated with appetite, insulin signaling, and brain plasticity Marlena Fejzo, Xinran Wang, Julia Zöllner, Natàlia Pujol Gualdo, and 25 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5487737/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 14 Apr, 2026 Read the published version in Nature Genetics → Version 1 posted You are reading this latest preprint version Abstract While most pregnancies are affected by nausea and vomiting, hyperemesis gravidarum (HG) is at the severe end of the clinical spectrum and is associated with dehydration, undernutrition, and adverse maternal, fetal, and child outcomes. Herein we performed a multi-ancestry genome-wide association study (GWAS) of severe nausea and vomiting of pregnancy of 10,974 cases and 461,461 controls across European, Asian, African, and Latino ancestries. We identified ten significantly associated loci, of which six were novel ( SLITRK1 , SYN3 , IGSF11 , FSHB , TCF7L2 , and CDH9), and confirmed previous genome-wide significant associations with risk genes GDF15 , IGFBP7 , PGR , and GFRAL . In a spatiotemporal analysis of placental development, GDF15 and TCF7L2 were expressed primarily in extra villous trophoblast, and using a weighted linear model of maternal, paternal, and fetal effects, we confirmed opposing effects for GDF15 between maternal and fetal genotype. Conversely, IGFBP7 and PGR were primarily expressed in developing maternal spiral arteries during placentation, with effects limited to the maternal genome. Risk loci were found to be under significant evolutionary selection, with the strongest effects on nausea and vomiting mid-pregnancy. Selected loci were associated with abnormal pregnancy weight gain, pregnancy duration, birth weight, head circumference, and pre-eclampsia. Potential roles for candidate genes in appetite, insulin signaling, and brain plasticity provide new pathways to explore etiological mechanisms and novel therapeutic avenues. Biological sciences/Genetics/Genetic association study/Genome-wide association studies Health sciences/Diseases/Reproductive disorders Full Text Additional Declarations Yes there is potential Competing Interest. The authors declare the existence of financial/non-financial competing interests. MF: Hyperemesis Education and Research (HER) Foundation (voluntary, unpaid Board member and Research Director); Harmonia Healthcare (CSO, stock, paid consultant); NGM Biosciences (stock, paid consultant); Foundation for Women's Health (Board member, voluntary, unpaid). Tables 1 to 3 are available in the Supplementary Files section Supplementary Files TABLES13.docx SUPPLEMENTARYTABLESS16.docx Cite Share Download PDF Status: Published Journal Publication published 14 Apr, 2026 Read the published version in Nature Genetics → 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-5487737","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":390071103,"identity":"a6348d3e-277f-4273-ab59-3a0c1c85d3c6","order_by":0,"name":"Marlena Fejzo","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA2UlEQVRIie3RoQoCMRjA8cFg6WRNJsL5BMI3BDH4MFsxa7touqRYFR/BIgwuT4RLd1hPDF6yCcZruml3i4L7lzH4fmxjCIVCvxjWCBAaR9RuxNSHEGHJJO7MLQFPYjoOQNvVh/RTrGdNgqU67eSjBtSjbf2dDHMigBVEZtVdMXMxvtkKB7kuAHgaGVLuLRFwcZGcPkCmTKp1qRpPEiE4pDAAusx8TyHA54WIWdXKRuZZHm/J8Y03yTOiq1Kdm2Tco10HMZHPZ7D3JHOO23D9Xqj2mg6FQqE/7AWt4UWcjierPAAAAABJRU5ErkJggg==","orcid":"https://orcid.org/0000-0001-6800-687X","institution":"Center for Genetic Epidemiology, Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Marlena","middleName":"","lastName":"Fejzo","suffix":""},{"id":390071104,"identity":"d52a844a-736f-4dd7-86a3-c0cdde754fb1","order_by":1,"name":"Xinran Wang","email":"","orcid":"https://orcid.org/0000-0001-9670-3939","institution":"University of Southern California","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Xinran","middleName":"","lastName":"Wang","suffix":""},{"id":390071105,"identity":"177c4a70-a58b-4c4a-8d5b-f4eb437d1577","order_by":2,"name":"Julia Zöllner","email":"","orcid":"https://orcid.org/0000-0002-9072-9131","institution":"University College London","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Julia","middleName":"","lastName":"Zöllner","suffix":""},{"id":390071106,"identity":"583a7413-ef4d-4916-a38f-0e4b0ff7d758","order_by":3,"name":"Natàlia Pujol Gualdo","email":"","orcid":"https://orcid.org/0000-0001-6428-8427","institution":"Estonian Genome Centre, Institute of Genomics, University of Tartu, Tartu, Estonia","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Natàlia","middleName":"Pujol","lastName":"Gualdo","suffix":""},{"id":390071107,"identity":"2b89ff22-f97f-462e-82d4-7d12af4c9e42","order_by":4,"name":"Triin Laisk","email":"","orcid":"https://orcid.org/0000-0003-1501-9030","institution":"University of Tartu","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Triin","middleName":"","lastName":"Laisk","suffix":""},{"id":390071108,"identity":"a3a0977c-596f-4336-bd7d-cad78f25f41d","order_by":5,"name":"Sarah Finer","email":"","orcid":"https://orcid.org/0000-0002-2684-4653","institution":"Queen Mary University of London","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Sarah","middleName":"","lastName":"Finer","suffix":""},{"id":390071109,"identity":"89d07c8e-6f82-4a0d-af85-a79799c73f6e","order_by":6,"name":"David van Heel","email":"","orcid":"https://orcid.org/0000-0002-0637-2265","institution":"Queen Mary University of London","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"David","middleName":"van","lastName":"Heel","suffix":""},{"id":390071110,"identity":"1b18a49e-eea5-4427-8dfc-25281355fabd","order_by":7,"name":"Genes \u0026 Health Research Team","email":"","orcid":"","institution":"Genes \u0026 Health Research Team","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Genes","middleName":"\u0026 Health Research","lastName":"Team","suffix":""},{"id":390071111,"identity":"e1329dbf-8eea-4d0e-aee4-adbad7091b6e","order_by":8,"name":"Ben Brumpton","email":"","orcid":"https://orcid.org/0000-0002-3058-1059","institution":"Norwegian University of Science and Technology","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Ben","middleName":"","lastName":"Brumpton","suffix":""},{"id":390071112,"identity":"98b7ac7a-42f5-489c-b550-748be8d847ee","order_by":9,"name":"Laxmi Bhatta","email":"","orcid":"","institution":"K.G. 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The authors declare the existence of financial/non-financial competing interests. MF: Hyperemesis Education and Research (HER) Foundation (voluntary, unpaid Board member and Research Director); Harmonia Healthcare (CSO, stock, paid consultant); NGM Biosciences (stock, paid consultant); Foundation for Women's Health (Board member, voluntary, unpaid).\u003c/p\u003e\n\u003cp\u003eTables 1 to 3 are available in the Supplementary Files section\u003c/p\u003e","formattedTitle":"Multi-ancestry genome-wide association study of severe pregnancy nausea and vomiting identifies risk loci associated with appetite, insulin signaling, and brain plasticity","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":false,"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":"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":"","lastPublishedDoi":"10.21203/rs.3.rs-5487737/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5487737/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eWhile most pregnancies are affected by nausea and vomiting, hyperemesis gravidarum (HG) is at the severe end of the clinical spectrum and is associated with dehydration, undernutrition, and adverse maternal, fetal, and child outcomes. Herein we performed a multi-ancestry genome-wide association study (GWAS) of severe nausea and vomiting of pregnancy of 10,974 cases and 461,461 controls across European, Asian, African, and Latino ancestries. We identified ten significantly associated loci, of which six were novel (\u003cem\u003eSLITRK1\u003c/em\u003e, \u003cem\u003eSYN3\u003c/em\u003e, \u003cem\u003eIGSF11\u003c/em\u003e, \u003cem\u003eFSHB\u003c/em\u003e, \u003cem\u003eTCF7L2\u003c/em\u003e, and \u003cem\u003eCDH9), \u003c/em\u003eand confirmed previous genome-wide significant associations with risk genes \u003cem\u003eGDF15\u003c/em\u003e, \u003cem\u003eIGFBP7\u003c/em\u003e, \u003cem\u003ePGR\u003c/em\u003e, and \u003cem\u003eGFRAL\u003c/em\u003e. In a spatiotemporal analysis of placental development, \u003cem\u003eGDF15\u003c/em\u003e and \u003cem\u003eTCF7L2\u003c/em\u003e were expressed primarily in extra villous trophoblast, and using a weighted linear model of maternal, paternal, and fetal effects, we confirmed opposing effects for \u003cem\u003eGDF15\u003c/em\u003e between maternal and fetal genotype. Conversely, \u003cem\u003eIGFBP7\u003c/em\u003e and \u003cem\u003ePGR \u003c/em\u003ewere primarily expressed in developing maternal spiral arteries during placentation, with effects limited to the maternal genome. Risk loci were found to be under significant evolutionary selection, with the strongest effects on nausea and vomiting mid-pregnancy. Selected loci were associated with abnormal pregnancy weight gain, pregnancy duration, birth weight, head circumference, and pre-eclampsia. Potential roles for candidate genes in appetite, insulin signaling, and brain plasticity provide new pathways to explore etiological mechanisms and novel therapeutic avenues.\u003c/p\u003e","manuscriptTitle":"Multi-ancestry genome-wide association study of severe pregnancy nausea and vomiting identifies risk loci associated with appetite, insulin signaling, and brain plasticity","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-12-16 11:09:00","doi":"10.21203/rs.3.rs-5487737/v1","editorialEvents":[],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"nature-genetics","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"ng","sideBox":"Learn more about [Nature Genetics](http://www.nature.com/ng/)","snPcode":"","submissionUrl":"","title":"Nature Genetics","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature Research","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"7090bb2d-03e0-4465-ab04-2cc8fd45f1b4","owner":[],"postedDate":"December 16th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":41580808,"name":"Biological sciences/Genetics/Genetic association study/Genome-wide association studies"},{"id":41580809,"name":"Health sciences/Diseases/Reproductive disorders"}],"tags":[],"updatedAt":"2026-04-15T07:08:05+00:00","versionOfRecord":{"articleIdentity":"rs-5487737","link":"https://doi.org/10.1038/s41588-026-02564-4","journal":{"identity":"nature-genetics","isVorOnly":false,"title":"Nature Genetics"},"publishedOn":"2026-04-14 04:00:00","publishedOnDateReadable":"April 14th, 2026"},"versionCreatedAt":"2024-12-16 11:09:00","video":"","vorDoi":"10.1038/s41588-026-02564-4","vorDoiUrl":"https://doi.org/10.1038/s41588-026-02564-4","workflowStages":[]},"version":"v1","identity":"rs-5487737","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5487737","identity":"rs-5487737","version":["v1"]},"buildId":"ehx78VzkSd0WSzXnipQa-","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}