An Updated Polygenic Index Repository: Expanded Phenotypes, New Cohorts, and Improved Causal Inference

An Updated Polygenic Index Repository: Expanded Phenotypes, New Cohorts, and Improved Causal Inference | 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 Resource An Updated Polygenic Index Repository: Expanded Phenotypes, New Cohorts, and Improved Causal Inference Aysu Okbay, Robel Alemu, Anastasia Terskaya, Matthew Howell, Junming Guan, and 47 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7828579/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 Polygenic indexes (PGIs) — DNA-based predictors of individual phenotypes — have become essential tools across biomedical and social sciences. We introduce Version 2 of the Polygenic Index Repository, which expands phenotype coverage from 47 to 61, increases the number of participating datasets from 11 to 20, and adopts a more consistent and improved methodology for PGI construction. For 16 phenotypes, we leverage summary statistics from an updated GWAS meta-analysis with greater statistical power compared to the original release, thereby improving the PGI’s predictive power. To improve power for family-based analyses, we provide imputed parental PGIs in all datasets with first-degree relatives and offer a framework for interpreting results from analyses that control for parental PGIs. We illustrate the utility of parental PGIs using two applications: (1) comparing PGI associations with and without parental PGI controls for all phenotypes in two Repository datasets with family data, and (2) for BMI and diastolic blood pressure, exploring the contribution of causal versus non-causal components of PGI associations to the imperfect portability of PGIs across subgroups within a genetic ancestry. Collectively, the updates enhance predictive performance, broaden the Repository’s scope, and introduce novel resources that reduce confounding bias and improve interpretability. Biological sciences/Genetics/Genomics Biological sciences/Biological techniques/Genomic analysis/Population genetics/Genetic variation Full Text Additional Declarations Yes there is potential Competing Interest. A.S.Y. serves as an advisor to and holds equity in Herasight, LLC. A.K. and members of the 23andMe Research Team are current or former employees of 23andMe, Inc. and hold stock or stock options in 23andMe. The authors declare no other competing interests. Supplementary Files SupplementaryNote.pdf Supplementary Note SupplementaryTables.xlsx Supplementary Tables 1-17 SupplementaryMethods.pdf Supplementary Methods and Polygenic Index Repository User Guide SupplementaryFigures.pdf 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-7828579","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Resource","associatedPublications":[],"authors":[{"id":527773031,"identity":"55b53dce-649d-4f00-8033-2173b62d20d7","order_by":0,"name":"Aysu Okbay","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAApUlEQVRIiWNgGAWjYHACZmYgIQdmPiBFizGYmUCKlsQGorXwNzAfNi6oOZy+4UYC2wOitEgcYEtOnnHscC5QC7sBcQ47wGN8mIftcO7MGQlsEkRpkQdr+Xc4XZJoLQZALcm8bYcT+CWI1WJ4mC3ZeGZfumE/z8M24rTIHW8+LF3wzVqejT35mMQHYrQwMIPJZiBmbCBKAwzUkaR6FIyCUTAKRhgAAIFmLPhuIVZLAAAAAElFTkSuQmCC","orcid":"https://orcid.org/0000-0002-5170-7781","institution":"Genetic Epidemiology, Department of Psychiatry, Amsterdam University Medical Center","correspondingAuthor":true,"prefix":"","firstName":"Aysu","middleName":"","lastName":"Okbay","suffix":""},{"id":527773032,"identity":"36ec82d2-5ede-48dc-97be-48100811910c","order_by":1,"name":"Robel Alemu","email":"","orcid":"https://orcid.org/0000-0003-3795-3983","institution":"University of California Los Angeles","correspondingAuthor":false,"prefix":"","firstName":"Robel","middleName":"","lastName":"Alemu","suffix":""},{"id":527773033,"identity":"8e94291e-01dc-44f5-b235-11c2545a0887","order_by":2,"name":"Anastasia Terskaya","email":"","orcid":"","institution":"Universidad de Barcelona","correspondingAuthor":false,"prefix":"","firstName":"Anastasia","middleName":"","lastName":"Terskaya","suffix":""},{"id":527773034,"identity":"7b1391ba-f158-4592-9004-2cb301624282","order_by":3,"name":"Matthew Howell","email":"","orcid":"https://orcid.org/0009-0007-4960-2095","institution":"UCLA Anderson School of Management","correspondingAuthor":false,"prefix":"","firstName":"Matthew","middleName":"","lastName":"Howell","suffix":""},{"id":527773035,"identity":"49f7ff51-cff0-44de-a03f-2596f5fc1aa9","order_by":4,"name":"Junming Guan","email":"","orcid":"","institution":"UCLA Anderson School of Management","correspondingAuthor":false,"prefix":"","firstName":"Junming","middleName":"","lastName":"Guan","suffix":""},{"id":527773036,"identity":"375f9f58-6299-4b5d-b10b-8640cea4be32","order_by":5,"name":"Harry Sands","email":"","orcid":"","institution":"Bucknell University","correspondingAuthor":false,"prefix":"","firstName":"Harry","middleName":"","lastName":"Sands","suffix":""},{"id":527773037,"identity":"62cb174d-7a81-41cc-80f3-9931f8cf933c","order_by":6,"name":"Aaron Kleinman","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Aaron","middleName":"","lastName":"Kleinman","suffix":""},{"id":527773038,"identity":"427d8a23-b856-4bfa-b0ca-b793707cc46f","order_by":7,"name":"23andMe Research Team","email":"","orcid":"","institution":"23andMe, Inc.","correspondingAuthor":false,"prefix":"","firstName":"23andMe","middleName":"Research","lastName":"Team","suffix":""},{"id":527773039,"identity":"19eea1fa-f787-4222-b1f9-eae6349f063c","order_by":8,"name":"David Bann","email":"","orcid":"https://orcid.org/0000-0002-6454-626X","institution":"University College London","correspondingAuthor":false,"prefix":"","firstName":"David","middleName":"","lastName":"Bann","suffix":""},{"id":527773040,"identity":"d3791fd0-6f8e-4fdf-83bf-6f74fee77e03","order_by":9,"name":"Tim Morris","email":"","orcid":"https://orcid.org/0000-0001-8178-6815","institution":"University of Bristol","correspondingAuthor":false,"prefix":"","firstName":"Tim","middleName":"","lastName":"Morris","suffix":""},{"id":527773041,"identity":"7c1af5e9-2db7-4933-b767-adf5f2d0eba3","order_by":10,"name":"George B. 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A.K. and members of the 23andMe Research Team are current or former employees of 23andMe, Inc. and hold stock or stock options in 23andMe. The authors declare no other competing interests.","formattedTitle":"An Updated Polygenic Index Repository: Expanded Phenotypes, New Cohorts, and Improved Causal Inference","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":"","lastPublishedDoi":"10.21203/rs.3.rs-7828579/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7828579/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Polygenic indexes (PGIs) — DNA-based predictors of individual phenotypes — have become essential tools across biomedical and social sciences. We introduce Version 2 of the Polygenic Index Repository, which expands phenotype coverage from 47 to 61, increases the number of participating datasets from 11 to 20, and adopts a more consistent and improved methodology for PGI construction. For 16 phenotypes, we leverage summary statistics from an updated GWAS meta-analysis with greater statistical power compared to the original release, thereby improving the PGI’s predictive power. To improve power for family-based analyses, we provide imputed parental PGIs in all datasets with first-degree relatives and offer a framework for interpreting results from analyses that control for parental PGIs. We illustrate the utility of parental PGIs using two applications: (1) comparing PGI associations with and without parental PGI controls for all phenotypes in two Repository datasets with family data, and (2) for BMI and diastolic blood pressure, exploring the contribution of causal versus non-causal components of PGI associations to the imperfect portability of PGIs across subgroups within a genetic ancestry. Collectively, the updates enhance predictive performance, broaden the Repository’s scope, and introduce novel resources that reduce confounding bias and improve interpretability.","manuscriptTitle":"An Updated Polygenic Index Repository: Expanded Phenotypes, New Cohorts, and Improved Causal Inference","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-10-13 11:44:30","doi":"10.21203/rs.3.rs-7828579/v1","editorialEvents":[],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"nature-human-behaviour","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"nathumbehav","sideBox":"Learn more about [Nature Human Behaviour](http://www.nature.com/nathumbehav/)","snPcode":"","submissionUrl":"","title":"Nature Human Behaviour","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature Research","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"16c73781-fc1d-411f-a266-0d1bad3f61c4","owner":[],"postedDate":"October 13th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":56103425,"name":"Biological sciences/Genetics/Genomics"},{"id":56103426,"name":"Biological sciences/Biological techniques/Genomic analysis/Population genetics/Genetic variation"}],"tags":[],"updatedAt":"2026-02-06T17:41:18+00:00","versionOfRecord":[],"versionCreatedAt":"2025-10-13 11:44:30","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7828579","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7828579","identity":"rs-7828579","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}