Parent-of-Origin inference and its role in the genetic architecture of complex traits: evidence from ~265,000 individuals

Parent-of-Origin inference and its role in the genetic architecture of complex traits: evidence from ~265,000 individuals | 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 Biological Sciences - Article Parent-of-Origin inference and its role in the genetic architecture of complex traits: evidence from ~265,000 individuals Zoltán Kutalik, Robin Hofmeister, Theo Cavinato, Roya Karimi, and 10 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5871891/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 06 Aug, 2025 Read the published version in Nature → Version 1 posted You are reading this latest preprint version Abstract Parent-of-origin effects (POEs) occur when the impact of a genetic variant depends on its parental origin. Traditionally linked to genomic imprinting, these effects are believed to have evolved from parental conflict over resource allocation to offspring, which results in opposing parental genetic influences. Despite their potential importance, POEs remain heavily understudied in complex traits, largely due to the lack of parental genomes. Here, we present a multi-step approach to infer the parent-of-origin of alleles without parental genomes, leveraging inter-chromosomal phasing, mitochondrial and chromosome X data, and sibling-based crossover inference. Applied to the UK Biobank (discovery cohort) and Estonian Biobank (replication cohort), this scalable approach enabled parent-of-origin inference for up to 221,062 individuals, representing the largest dataset of its kind. GWAS scans in the UK Biobank for more than 60 complex traits and over 2,400 protein levels contrasting maternal and paternal effects identified over 30 novel POEs and confirmed more than 50% of testable known associations. Notably, approximately half of our POEs exhibited a bi-polar pattern, where maternal and paternal alleles exert conflicting effects. These effects were particularly prevalent for traits related to growth (e.g., IGF-1, height, fat-free mass) and metabolism (e.g., type 2 diabetes, triglycerides, glucose). Replication in the Estonian Biobank and in 45,402 offspring from the Norwegian Mother, Father and Child Cohort Study validated over 75% of testable associations. Overall, our findings shed new light on the influence of POEs on diverse complex traits and align with the parental conflict hypothesis, providing compelling evidence for this understudied evolutionary phenomenon. Biological sciences/Computational biology and bioinformatics/Statistical methods Biological sciences/Genetics/Genetic association study/Genome-wide association studies Biological sciences/Genetics/Haplotypes Biological sciences/Genetics/Epigenetics/Imprinting Full Text Additional Declarations Yes there is potential Competing Interest. Olivier Delaneau is a current employee of Regeneron Genetics Center. The others authors declare no competing interests. Supplementary Files POEsHofmeisteretal2025supplements.pdf Supplementary information Cite Share Download PDF Status: Published Journal Publication published 06 Aug, 2025 Read the published version in Nature → 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. 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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-5871891","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Biological Sciences - Article","associatedPublications":[],"authors":[{"id":405617867,"identity":"4d6e6d45-cb98-4974-933f-76b8fe41c4e5","order_by":0,"name":"Zoltán 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The others authors declare no competing interests.","formattedTitle":"Parent-of-Origin inference and its role in the genetic architecture of complex traits: evidence from ~265,000 individuals","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-5871891/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5871891/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Parent-of-origin effects (POEs) occur when the impact of a genetic variant depends on its parental origin. Traditionally linked to genomic imprinting, these effects are believed to have evolved from parental conflict over resource allocation to offspring, which results in opposing parental genetic influences. Despite their potential importance, POEs remain heavily understudied in complex traits, largely due to the lack of parental genomes.\r\nHere, we present a multi-step approach to infer the parent-of-origin of alleles without parental genomes, leveraging inter-chromosomal phasing, mitochondrial and chromosome X data, and sibling-based crossover inference. Applied to the UK Biobank (discovery cohort) and Estonian Biobank (replication cohort), this scalable approach enabled parent-of-origin inference for up to 221,062 individuals, representing the largest dataset of its kind.\r\nGWAS scans in the UK Biobank for more than 60 complex traits and over 2,400 protein levels contrasting maternal and paternal effects identified over 30 novel POEs and confirmed more than 50% of testable known associations. Notably, approximately half of our POEs exhibited a bi-polar pattern, where maternal and paternal alleles exert conflicting effects. These effects were particularly prevalent for traits related to growth (e.g., IGF-1, height, fat-free mass) and metabolism (e.g., type 2 diabetes, triglycerides, glucose). Replication in the Estonian Biobank and in 45,402 offspring from the Norwegian Mother, Father and Child Cohort Study validated over 75% of testable associations.\r\nOverall, our findings shed new light on the influence of POEs on diverse complex traits and align with the parental conflict hypothesis, providing compelling evidence for this understudied evolutionary phenomenon.","manuscriptTitle":"Parent-of-Origin inference and its role in the genetic architecture of complex traits: evidence from ~265,000 individuals","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-01-24 03:52:23","doi":"10.21203/rs.3.rs-5871891/v1","editorialEvents":[],"status":"published","journal":{"display":false,"email":"[email protected]","identity":"nature","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"nature","sideBox":"Learn more about [Nature](http://www.nature.com/nature/)","snPcode":"","submissionUrl":"","title":"Nature","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"47424cea-5807-48c8-a724-3067eafcc22e","owner":[],"postedDate":"January 24th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":43249593,"name":"Biological sciences/Computational biology and bioinformatics/Statistical methods"},{"id":43249594,"name":"Biological sciences/Genetics/Genetic association study/Genome-wide association studies"},{"id":43249595,"name":"Biological sciences/Genetics/Haplotypes"},{"id":43249596,"name":"Biological sciences/Genetics/Epigenetics/Imprinting"}],"tags":[],"updatedAt":"2025-08-07T07:33:12+00:00","versionOfRecord":{"articleIdentity":"rs-5871891","link":"https://doi.org/10.1038/s41586-025-09357-5","journal":{"identity":"nature","isVorOnly":false,"title":"Nature"},"publishedOn":"2025-08-06 04:00:00","publishedOnDateReadable":"August 6th, 2025"},"versionCreatedAt":"2025-01-24 03:52:23","video":"","vorDoi":"10.1038/s41586-025-09357-5","vorDoiUrl":"https://doi.org/10.1038/s41586-025-09357-5","workflowStages":[]},"version":"v1","identity":"rs-5871891","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5871891","identity":"rs-5871891","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}