Monogenic and Polygenic Contributions to Cardiomyopathy and Heart Failure Across Diverse Populations

Monogenic and Polygenic Contributions to Cardiomyopathy and Heart Failure Across Diverse Populations | 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 Monogenic and Polygenic Contributions to Cardiomyopathy and Heart Failure Across Diverse Populations Naveen Pereira, Jia Tan, Ozan Dikilitas, Marta Figueiral, Jennifer Tan-Arroyo, and 9 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9581360/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 Pathogenic variants in cardiomyopathy genes confer substantial disease risk, yet clinical penetrance varies widely. The population-level prevalence, age-specific penetrance, and the extent to which polygenic susceptibility modifies disease risk across diverse ancestries remain poorly defined. This population-based cohort study leveraged genome sequencing and linked electronic health record data from the All of Us Research Program (n=414,830). This study found that P/LP variants in cardiomyopathy-associated genes were present in 0.91% of participants (95% CI, 0.88%–0.94%), with similar prevalence across ancestry groups. Compared with non-carriers, variant carriers had significantly higher odds of all-cause heart failure (ACHF, OR, 2.58; 95% CI, 2.31–2.89), non-ischemic heart failure (NIHF, OR, 2.74; 95% CI, 2.42–3.10), and non-ischemic cardiomyopathy (NICM, OR, 4.99; 95% CI, 4.44–5.63). Among carriers, by age 50 years, 24.5% (95% CI, 14.5%–33.4%) developed ACHF, 17.2% (95% CI, 8.8%–24.8%) developed NIHF, and 30.1% (95% CI, 19.5%–40.2%) developed NICM. Higher polygenic risk for heart failure was independently associated with increased risk of ACHF (OR, 1.81; 95% CI, 1.74–1.89), NIHF (OR, 1.66; 95% CI, 1.58–1.75), and NICM (OR, 1.69; 95% CI, 1.59–1.80). Among carriers with elevated polygenic risk, odds of disease were substantially higher than among non-carriers at average polygenic risk (ACHF: OR, 4.71; 95% CI, 4.17–5.32; NIHF: OR, 4.56; 95% CI, 3.99–5.22; NICM: OR, 8.51; 95% CI, 7.44–9.73). Results showed that P/LP variants in cardiomyopathy genes were relatively common in this large, ancestrally diverse cohort, and conferred increased risk of cardiomyopathy and HF, with incomplete but clinically meaningful penetrance. Polygenic risk for HF independently and additively increased disease risk across ancestries. Integrating both may improve risk stratification and enable more precise, equitable care. Health sciences/Medical research/Genetics research Health sciences/Diseases/Cardiovascular diseases/Cardiomyopathies Health sciences/Medical research/Outcomes research Health sciences/Diseases/Cardiovascular diseases/Heart failure Health sciences/Medical research/Translational research Full Text Additional Declarations There is NO Competing Interest. All data analyzed in this publication were collected from participants who provided informed consent to the All of Us Research Program. Participant information was de-identified in accordance with program protocols and applicable regulations to protect privacy and confidentiality. Supplementary Files SupplementalTableS1.xlsx Supplemental Table S1 SupplementalFigureS3.pdf Supplemental Figure S3 SupplementalTableS2.xlsx Supplemental Table S2 SupplementalTableS7.xlsx Supplemental Table S7 SupplementalFigureS1.pdf Supplemental Figure S1 SupplementalFigureS2.pdf Supplemental Figure S2 SupplementalTableS5.xlsx Supplemental Table S5 SupplementalTableS4.xlsx Supplemental Table S4 SupplementalTableS3.xlsx Supplemental Table S3 SupplementalTableS6.pdf Supplemental Table S6 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-9581360","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":634270213,"identity":"3c21bbbe-8df5-4c62-b310-34e4ccdc39ed","order_by":0,"name":"Naveen Pereira","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABCElEQVRIiWNgGAWjYBAC+wYgkQDEBgfAfBuoOBtuLWCVIC0WEC1pRGoBGw9hHCZCy/Hehw8e7rFjsDl+xvDBxx3no/lnJB9g+FB2GKcW+57jxgYJz5IZzM7kGBvOPHM7d8aNtATGGedwazGQSGOTSDjAzGB2IC1Nmrftdm7DjRwDZt42PFrkn7H/SDhQz2B8/ln6779t53Lng7T8xadFgo2NIeHAYQbDG8nHmBnbDuRuAGlhxKeFJ40Z6LDjPIY3Hh+W7G1Lzt145lnCwZ5z6bi1sB9j/PjjQLWcwfnExg8/2+xy5x1PPvjgR5k1Ti0wwINgCiQwHCCoHhXwk6phFIyCUTAKhjsAAIHVYLLmZRugAAAAAElFTkSuQmCC","orcid":"","institution":"Mayo Clinic","correspondingAuthor":true,"prefix":"","firstName":"Naveen","middleName":"","lastName":"Pereira","suffix":""},{"id":634270214,"identity":"ef1c48f7-6219-4705-87c0-56e56d77a9db","order_by":1,"name":"Jia Tan","email":"","orcid":"https://orcid.org/0000-0002-7727-2616","institution":"Mayo Clinic","correspondingAuthor":false,"prefix":"","firstName":"Jia","middleName":"","lastName":"Tan","suffix":""},{"id":634270215,"identity":"948719af-bea6-4451-b798-0b10d69ecedd","order_by":2,"name":"Ozan Dikilitas","email":"","orcid":"https://orcid.org/0000-0002-9906-8608","institution":"Mayo Clinic","correspondingAuthor":false,"prefix":"","firstName":"Ozan","middleName":"","lastName":"Dikilitas","suffix":""},{"id":634270216,"identity":"c2038951-d896-441b-9f07-77de12b4bab0","order_by":3,"name":"Marta Figueiral","email":"","orcid":"","institution":"Mayo Clinic","correspondingAuthor":false,"prefix":"","firstName":"Marta","middleName":"","lastName":"Figueiral","suffix":""},{"id":634270217,"identity":"4485c246-012b-48c5-81c7-8fbf0cf7fddf","order_by":4,"name":"Jennifer Tan-Arroyo","email":"","orcid":"","institution":"Mayo Clinic","correspondingAuthor":false,"prefix":"","firstName":"Jennifer","middleName":"","lastName":"Tan-Arroyo","suffix":""},{"id":634270218,"identity":"935c59e4-92bb-48f7-98f1-10efe968adb6","order_by":5,"name":"Rory Olson","email":"","orcid":"","institution":"Mayo Clinic","correspondingAuthor":false,"prefix":"","firstName":"Rory","middleName":"","lastName":"Olson","suffix":""},{"id":634270219,"identity":"5e8f028c-5602-42af-b7b7-bb17f1671b54","order_by":6,"name":"Deepak Panwar","email":"","orcid":"","institution":"Mayo Clinic","correspondingAuthor":false,"prefix":"","firstName":"Deepak","middleName":"","lastName":"Panwar","suffix":""},{"id":634270220,"identity":"9b7e7d14-fdf6-4615-9eeb-9b25ae18ff5f","order_by":7,"name":"Jenny Cao","email":"","orcid":"","institution":"Mayo Clinic","correspondingAuthor":false,"prefix":"","firstName":"Jenny","middleName":"","lastName":"Cao","suffix":""},{"id":634270221,"identity":"1641ed8f-dee9-4e29-91d5-6f73ea309292","order_by":8,"name":"Akshatha Srinivas","email":"","orcid":"","institution":"Mayo Clinic","correspondingAuthor":false,"prefix":"","firstName":"Akshatha","middleName":"","lastName":"Srinivas","suffix":""},{"id":634270222,"identity":"c798d2b3-cd64-4d70-81c2-05585de2cca2","order_by":9,"name":"Yao Xiao","email":"","orcid":"","institution":"Mayo Clinic","correspondingAuthor":false,"prefix":"","firstName":"Yao","middleName":"","lastName":"Xiao","suffix":""},{"id":634270223,"identity":"481736ea-e9d9-421b-9e27-814806c62736","order_by":10,"name":"Marcella Venettozzi","email":"","orcid":"","institution":"Mayo Clinic","correspondingAuthor":false,"prefix":"","firstName":"Marcella","middleName":"","lastName":"Venettozzi","suffix":""},{"id":634270224,"identity":"8aeea60d-fb48-462f-a999-d83c1e05a13c","order_by":11,"name":"Filippo Pinto e Vairo","email":"","orcid":"","institution":"Mayo Clinic","correspondingAuthor":false,"prefix":"","firstName":"Filippo","middleName":"Pinto e","lastName":"Vairo","suffix":""},{"id":634270225,"identity":"5ab8bf93-fd5d-422b-8581-346b1193b7cb","order_by":12,"name":"Daniel Schaid","email":"","orcid":"","institution":"Mayo Clinic","correspondingAuthor":false,"prefix":"","firstName":"Daniel","middleName":"","lastName":"Schaid","suffix":""},{"id":634270226,"identity":"8bd37488-6c22-4bbf-a598-904bfa68e4b2","order_by":13,"name":"Eric W. 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to the All of Us Research Program. Participant information was de-identified in accordance with program protocols and applicable regulations to protect privacy and confidentiality.\u003c/p\u003e","formattedTitle":"Monogenic and Polygenic Contributions to Cardiomyopathy and Heart Failure Across Diverse Populations","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-9581360/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9581360/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Pathogenic variants in cardiomyopathy genes confer substantial disease risk, yet clinical penetrance varies widely. The population-level prevalence, age-specific penetrance, and the extent to which polygenic susceptibility modifies disease risk across diverse ancestries remain poorly defined. This population-based cohort study leveraged genome sequencing and linked electronic health record data from the All of Us Research Program (n=414,830). This study found that P/LP variants in cardiomyopathy-associated genes were present in 0.91% of participants (95% CI, 0.88%–0.94%), with similar prevalence across ancestry groups. Compared with non-carriers, variant carriers had significantly higher odds of all-cause heart failure (ACHF, OR, 2.58; 95% CI, 2.31–2.89), non-ischemic heart failure (NIHF, OR, 2.74; 95% CI, 2.42–3.10), and non-ischemic cardiomyopathy (NICM, OR, 4.99; 95% CI, 4.44–5.63). Among carriers, by age 50 years, 24.5% (95% CI, 14.5%–33.4%) developed ACHF, 17.2% (95% CI, 8.8%–24.8%) developed NIHF, and 30.1% (95% CI, 19.5%–40.2%) developed NICM. Higher polygenic risk for heart failure was independently associated with increased risk of ACHF (OR, 1.81; 95% CI, 1.74–1.89), NIHF (OR, 1.66; 95% CI, 1.58–1.75), and NICM (OR, 1.69; 95% CI, 1.59–1.80). Among carriers with elevated polygenic risk, odds of disease were substantially higher than among non-carriers at average polygenic risk (ACHF: OR, 4.71; 95% CI, 4.17–5.32; NIHF: OR, 4.56; 95% CI, 3.99–5.22; NICM: OR, 8.51; 95% CI, 7.44–9.73). Results showed that P/LP variants in cardiomyopathy genes were relatively common in this large, ancestrally diverse cohort, and conferred increased risk of cardiomyopathy and HF, with incomplete but clinically meaningful penetrance. Polygenic risk for HF independently and additively increased disease risk across ancestries. Integrating both may improve risk stratification and enable more precise, equitable care.","manuscriptTitle":"Monogenic and Polygenic Contributions to Cardiomyopathy and Heart Failure Across Diverse Populations","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-05-08 05:11:26","doi":"10.21203/rs.3.rs-9581360/v1","editorialEvents":[],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"nature-communications","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"NCOMMS","sideBox":"Learn more about [Nature Communications](http://www.nature.com/ncomms/)","snPcode":"","submissionUrl":"https://mts-ncomms.nature.com/","title":"Nature Communications","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature Communications","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"387d92e4-1810-48f9-a52c-c8974043ebc5","owner":[],"postedDate":"May 8th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":67500546,"name":"Health sciences/Medical research/Genetics research"},{"id":67500547,"name":"Health sciences/Diseases/Cardiovascular diseases/Cardiomyopathies"},{"id":67500548,"name":"Health sciences/Medical research/Outcomes research"},{"id":67500549,"name":"Health sciences/Diseases/Cardiovascular diseases/Heart failure"},{"id":67500550,"name":"Health sciences/Medical research/Translational research"}],"tags":[],"updatedAt":"2026-05-08T05:11:26+00:00","versionOfRecord":[],"versionCreatedAt":"2026-05-08 05:11:26","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9581360","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9581360","identity":"rs-9581360","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}