Maternal hypertension-related genes affect the fetal growth via placenta

Maternal hypertension-related genes affect the fetal growth via placenta | 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 Maternal hypertension-related genes affect the fetal growth via placenta Noriko Sato, Ayako Fudono, Chihiro Imai, Hidemi Takimoto, Iori Tarui, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-431082/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Low birth weight is associated with the development of cardio-metabolic diseases later in life1-4. A recent Mendelian Randomization Study concluded that the susceptibility of low-birth-weight infants to develop hypertension during adulthood is due to the inheritance of hypertension genes from the mother, and not to an unfavorable intrauterine environment5. Therein, it has been assumed that low birth weight is caused by maternal hypertension5,6, although there is no evidence to support such a linear relationship. In the present study, we have noted that most of blood pressure SNPs are related to vascular regulation7-9 and found that the relationship between maternal blood pressure-increasing polygenic score and reduction of offspring birth weight is mediated by a reduced growth of the placenta but not by the mother's high blood pressure. This suggests that the risk of hypertension of low-birth-weight infants may result from a poor placental environment. Maternal & Fetal Medicine Intrauterine programming Placenta Blood pressure Partitioned polygenic score Vascular genes Figures Figure 1 Figure 2 Figure 3 Full Text Additional Declarations There is NO Competing Interest. Supplementary Files SupplementaryTableNS.xlsx Supplementary Tables Supplementary Table 1. Association between maternal and fetal SBP-increasing PGS and various phenotypes Supplementary Table 2. Association between maternal or fetal DBP-increasing PGS and various phenotypes Supplementary Table 3. Association between maternal or fetal MAP-increasing PGS and various phenotypes Supplementary Table 4. Association between maternal or fetal PP-increasing PGS and various phenotypes Supplementary Table 5. Evaluation of the models for relationship between birth weight and maternal observational SBP Supplementary Table 6. Evaluation of the models for relationship between birth weight and maternal observational DBP Supplementary Table 7. Evaluation of the models for relationship between birth weight and maternal observational MAP Supplementary Table 8. Evaluation of the models for relationship between birth weight and maternal observational PP Supplementary Table 9. Genome-wide Significant loci for blood pressure phenotypes and classification based on vasculature relevance Supplementary Table 10. Variants constituting SBP-increasing PGS at p-value threshold of 1 x 10-6 and classification based on vasculature relevance Supplementary Table 11. Association between the partitioned maternal SBP-increasing PGS and placenta weight Supplementary Table 12. Association between the partitioned haplotype genetics scores and placenta weight Supplementary Table 13. Characteristics of participants included in this study SupplementaryFigure.pdf Supplementary Figures Fig. S1: The relationship between maternal BP in early gestation and offspring birth weight is not a negative linear association Fig. S2: The relationship between maternal BP in mid gestation and offspring birth weight is not a negative linear association Cite Share Download PDF Status: Posted 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-431082","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":22171078,"identity":"d6ce0988-9255-4c4f-9812-961a0d7dd520","order_by":0,"name":"Noriko Sato","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA+ElEQVRIiWNgGAWjYDADNvYGBoYEEOsAiODBq5ixAayF5wBIiwEJWhgkwFbAtOAB5vyHnz/4wGCTxyf5Ou3DA4Y/0XwHmB9+YJC5g1OL5Yw0w8YZDGnFbNK5m2cAHZY78wCbsQQDzzOcWgxuMBg28zAcTmwDagH5JXfDAQYzoF8O49Zy/vhHoJb/iW2SZ2Fa2L/h13IgB2TLgcQ2CV6YFh4CttzIKZw5wyC5mI0H5DAD49yZh3mKJRLw+eX88Q0fPlTY5cm3n93M+KNCLrfvePvGDx97cIcYVCMk3sHRwsAMxIk9BwhoYYBpgYMfhLWMglEwCkbBiAEAiXlUtKDg7IkAAAAASUVORK5CYII=","orcid":"https://orcid.org/0000-0002-0384-5362","institution":"Medical Research Institute, Tokyo Medical and Dental University","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Noriko","middleName":"","lastName":"Sato","suffix":""},{"id":22171079,"identity":"61a7ab71-3239-4010-b4ee-0b1dd5a54438","order_by":1,"name":"Ayako Fudono","email":"","orcid":"","institution":"Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Ayako","middleName":"","lastName":"Fudono","suffix":""},{"id":22171080,"identity":"29721fc7-1109-4f30-b918-9f3a31c58977","order_by":2,"name":"Chihiro Imai","email":"","orcid":"","institution":"Medical Research Institute, Tokyo Medical and Dental University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Chihiro","middleName":"","lastName":"Imai","suffix":""},{"id":22171081,"identity":"e843128b-2304-49c6-a5c5-89faee1db7ce","order_by":3,"name":"Hidemi Takimoto","email":"","orcid":"","institution":"National Institute of Health and Nutrition","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Hidemi","middleName":"","lastName":"Takimoto","suffix":""},{"id":22171082,"identity":"41622931-b403-4c7f-b4e6-1a0246cdb4c3","order_by":4,"name":"Iori Tarui","email":"","orcid":"","institution":"National Institute of Health and Nutrition","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Iori","middleName":"","lastName":"Tarui","suffix":""},{"id":22171083,"identity":"01495774-dc53-40aa-91e2-e56964abd9ad","order_by":5,"name":"Tomoko Aoyama","email":"","orcid":"","institution":"National Institute of Health and Nutrition","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Tomoko","middleName":"","lastName":"Aoyama","suffix":""},{"id":22171084,"identity":"7b275da8-284d-4e50-8bf5-0270d645fb6c","order_by":6,"name":"Satoshi Yago","email":"","orcid":"","institution":"Graduate School of Health Care Sciences, Tokyo Medical and Dental University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Satoshi","middleName":"","lastName":"Yago","suffix":""},{"id":22171085,"identity":"88dc5743-fcc6-4af5-a0f5-eabf2f7c3e3e","order_by":7,"name":"Motoko Okamitsu","email":"","orcid":"","institution":"Graduate School of Health Care Sciences, Tokyo Medical and Dental University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Motoko","middleName":"","lastName":"Okamitsu","suffix":""},{"id":22171086,"identity":"b377c7e0-2c3b-4881-8dbc-47a4faaf9c6c","order_by":8,"name":"Shuki Mizutani","email":"","orcid":"","institution":"Tokyo Medical and Dental University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Shuki","middleName":"","lastName":"Mizutani","suffix":""},{"id":22171087,"identity":"6193de12-3248-4bdc-8907-2e60e505f10e","order_by":9,"name":"Naoyuki Miyasaka","email":"","orcid":"","institution":"Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Naoyuki","middleName":"","lastName":"Miyasaka","suffix":""}],"badges":[],"createdAt":"2021-04-16 23:45:57","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-431082/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-431082/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":8291119,"identity":"853639e9-7100-476c-b81d-436cddf6509a","added_by":"auto","created_at":"2021-04-21 17:28:14","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":151387,"visible":true,"origin":"","legend":"Maternal SBP-increasing PGS associates with placenta weight rather than\nmeasured SBP.\na. Distribution of normalized maternal systolic blood pressure (SBP)-increasing\npolygenic score (PGS) constituted of a set of SNPs exceeding a GWAS association pvalue\nof 1.0 x 10-4 and the stratification according to the tertiles. b–i. Phenotype data\nacross maternal PGS tertiles. Each subject (n = 93) is shown in the box-and-whisker\nplots, with the boxes indicating the median and interquartile range and the whiskers\ndenoting the range. The observed SBP shown in b is the mean SBP during late\ngestation period, which was the most correlated with PGS among early, mid, and late\nperiods. Birth weight and placenta weight are adjusted for gestational age, fetal sex,\nand parity. All phenotype data are scaled to have zero mean and unit variance by Zscore\ntransformation. Regression coefficient (Est.), standing for the change per strata\nincrease, and P-value are shown.","description":"","filename":"Figure120210408.png","url":"https://assets-eu.researchsquare.com/files/rs-431082/v1/ae531212858dd70150ab3832.png"},{"id":8290637,"identity":"d5bd2afc-d05e-4cab-8f3e-b9f1ac978e84","added_by":"auto","created_at":"2021-04-21 17:25:14","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":651466,"visible":true,"origin":"","legend":"The relationship between maternal BP in late gestation and offspring\nbirth weight is not a negative linear association\nAssociation between birth weight and mean late-gestational SBP (a), DBP (b),\nMAP (c), and PP (d), respectively. Each subject is included (n = 993) in the boxand-\nwhisker plots, with the boxes indicating the median and interquartile range and\nthe whiskers denoting the range. Birth weight is adjusted for gestational age, fetal\nsex, and parity and scaled to have zero mean and unit variance by Z-score\ntransformation. Regression lines are shown in red.","description":"","filename":"Figure2NS.png","url":"https://assets-eu.researchsquare.com/files/rs-431082/v1/9adda964544609f8ac049f27.png"},{"id":8291596,"identity":"2b35b4f8-3119-47b6-bb8a-277b13c0b96e","added_by":"auto","created_at":"2021-04-21 17:31:14","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":768914,"visible":true,"origin":"","legend":"Maternal “vasculature related” alleles among BP-increasing SNPs are\nprimarily responsible for reducing placenta weight\na. Venn diagram of 41 genome-wide significant single nucleotide polymorphisms\n(SNPs) for BP phenotypes. There is a considerable overlap of association across\nfour BP phenotypes, with a consistent direction of the effect, except for seven loci\nthat present opposite or unclear effect directions for DBP (indicated by †). SNPs are\nclassified into “vasculature-related” (red), “unlikely related” (blue), and “unknown”\n(green) groups, respectively, as described in the results and Supplementary Table 9.\nb. Relationship between total or partitioned genotypic allele counts and the placenta\nweight shown as scatter plots (n = 93). c, Relationship between the placenta weight\nand the haplotype allele counts for maternal transmitted, maternal non-transmitted,\nand paternal transmitted allele, respectively, shown as scatter plots (n = 93).\nPlacenta weight is adjusted for gestational age, fetal sex, and parity and scaled to\nhave zero mean and unit variance by Z-score transformation. Regression coefficient\n(Est.) and P-value are shown.","description":"","filename":"Figure3NS.png","url":"https://assets-eu.researchsquare.com/files/rs-431082/v1/d4f54dc8cbc85accb11ed999.png"},{"id":13624069,"identity":"812fa966-1f58-4882-a923-fd638615f6b4","added_by":"auto","created_at":"2021-09-17 07:21:05","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2133123,"visible":true,"origin":"","legend":"","description":"","filename":"ManuscriptNS.pdf","url":"https://assets-eu.researchsquare.com/files/rs-431082/v1_covered.pdf"},{"id":8292009,"identity":"87d50b5d-b5bd-487c-b523-25bdcc755e3f","added_by":"auto","created_at":"2021-04-21 17:34:30","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2081163,"visible":true,"origin":"","legend":"","description":"","filename":"ManuscriptNS.pdf","url":"https://assets-eu.researchsquare.com/files/rs-431082/v1_stamped.pdf"},{"id":8291118,"identity":"2199edbc-6090-41be-9521-5a91807781bb","added_by":"auto","created_at":"2021-04-21 17:28:14","extension":"xlsx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":94156,"visible":true,"origin":"","legend":"Supplementary Tables\n Supplementary Table 1. Association between maternal and fetal SBP-increasing PGS and various\nphenotypes\n Supplementary Table 2. Association between maternal or fetal DBP-increasing PGS and various\n phenotypes\n Supplementary Table 3. Association between maternal or fetal MAP-increasing PGS and various\n phenotypes\n Supplementary Table 4. Association between maternal or fetal PP-increasing PGS and various\n phenotypes\nSupplementary Table 5. Evaluation of the models for relationship between birth weight and maternal\n observational SBP\nSupplementary Table 6. Evaluation of the models for relationship between birth weight and maternal\n observational DBP\n Supplementary Table 7. Evaluation of the models for relationship between birth weight and maternal\nobservational MAP\n Supplementary Table 8. Evaluation of the models for relationship between birth weight and maternal\n observational PP\n Supplementary Table 9. Genome-wide Significant loci for blood pressure phenotypes and\n classification based on vasculature relevance\n Supplementary Table 10. Variants constituting SBP-increasing PGS at p-value threshold of 1 x 10-6\n and classification based on vasculature relevance\nSupplementary Table 11. Association between the partitioned maternal SBP-increasing PGS and\nplacenta weight\nSupplementary Table 12. Association between the partitioned haplotype genetics scores and placenta\n weight\nSupplementary Table 13. Characteristics of participants included in this study","description":"","filename":"SupplementaryTableNS.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-431082/v1/d368e82ada810c32498854c0.xlsx"},{"id":8291597,"identity":"1c80d546-d6a6-450c-bb78-825191963d55","added_by":"auto","created_at":"2021-04-21 17:31:14","extension":"pdf","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":1255401,"visible":true,"origin":"","legend":"Supplementary Figures\nFig. S1: The relationship between maternal BP in early gestation and offspring birth weight is not a\nnegative linear association\nFig. S2: The relationship between maternal BP in mid gestation and offspring birth weight is not a\n negative linear association","description":"","filename":"SupplementaryFigure.pdf","url":"https://assets-eu.researchsquare.com/files/rs-431082/v1/8f3536a14b83ea8a89ff453f.pdf"}],"financialInterests":"There is \u003cb\u003eNO\u003c/b\u003e Competing Interest.","formattedTitle":"Maternal hypertension-related genes affect the fetal growth via placenta","fulltext":[{"header":"Full Text","content":"This preprint is available for \u003ca href='/article/rs-431082/latest.pdf' target='_blank'\u003edownload as a PDF\u003c/a\u003e."}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Intrauterine programming, Placenta, Blood pressure, Partitioned polygenic score, Vascular genes","lastPublishedDoi":"10.21203/rs.3.rs-431082/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-431082/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Low birth weight is associated with the development of cardio-metabolic diseases later in life1-4. A recent Mendelian Randomization Study concluded that the susceptibility of low-birth-weight infants to develop hypertension during adulthood is due to the inheritance of hypertension genes from the mother, and not to an unfavorable intrauterine environment5. Therein, it has been assumed that low birth weight is caused by maternal hypertension5,6, although there is no evidence to support such a linear relationship. In the present study, we have noted that most of blood pressure SNPs are related to vascular regulation7-9 and found that the relationship between maternal blood pressure-increasing polygenic score and reduction of offspring birth weight is mediated by a reduced growth of the placenta but not by the mother\u0026#39;s high blood pressure. This suggests that the risk of hypertension of low-birth-weight infants may result from a poor placental environment.","manuscriptTitle":"Maternal hypertension-related genes affect the fetal growth via placenta","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2021-04-21 17:25:12","doi":"10.21203/rs.3.rs-431082/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"ed5dda3a-60fd-453d-a48a-86f40c7a8a40","owner":[],"postedDate":"April 21st, 2021","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":3806342,"name":"Maternal \u0026 Fetal Medicine"}],"tags":[],"updatedAt":"2021-05-04T17:12:58+00:00","versionOfRecord":[],"versionCreatedAt":"2021-04-21 17:25:12","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-431082","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-431082","identity":"rs-431082","version":["v1"]},"buildId":"ehx78VzkSd0WSzXnipQa-","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}