Rare coding variant architecture and gene discovery from 130,000 sequenced cases of atrial fibrillation

Rare coding variant architecture and gene discovery from 130,000 sequenced cases of atrial fibrillation | 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 Rare coding variant architecture and gene discovery from 130,000 sequenced cases of atrial fibrillation Sean Jurgens, Nobuyuki Enzan, Ian Dinsmore, Seung Hoan Choi, Jonathan Luo, and 102 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9191644/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 Rare coding genetic variants may exert large effects on risk of common disease, yet their contribution to disease architecture and their utility in gene prioritization remain limited by inadequate sample sizes. Here, we performed a massive-scale rare variant association study (RVAS), analyzing over 1.1 million sequenced participants among which 130,000 had atrial fibrillation (AF). Through a multi-mask burden testing approach, we identified 15 genes significantly associated with AF through rare large-effect variation. Integrative analyses revealed strong convergence between genes implicated by rare and common variation, and highlighted instances where RVAS data may aid in GWAS prioritization. Nevertheless, several RVAS genes were not among GWAS loci ( FAM189A2 , ACTC1 , FNIP1 , FBN1 ), or were not nominated through contemporary GWAS prioritization ( KDM5B , ZFP36L2 ). Finally, we observed that ultra-rare protein-disrupting variants - concentrated in a small number of large-effect size genes - explained at least 2% of AF susceptibility across European and African ancestry groups. These findings refine the genetic architecture of AF, while highlighting the value and cost of RVAS for genomic discovery in common disease. Biological sciences/Genetics/Genomics Biological sciences/Genetics/Genetic association study Health sciences/Diseases/Cardiovascular diseases/Arrhythmias/Atrial fibrillation Full Text Additional Declarations Yes there is potential Competing Interest. P.T.E. has received sponsored research support from Bayer AG, Bristol Myers Squibb, Pfizer, and Novo Nordisk, and he has consulted for Bayer AG. S.A.L. is a full-time employee of Novartis Institutes of BioMedical Research as of July 18, 2022. S.A.L. previously received sponsored research support from Bristol Myers Squibb, Pfizer, Boehringer Ingelheim, Fitbit, Medtronic, Premier, and IBM, and has consulted for Bristol Myers Squibb, Pfizer, Blackstone Life Sciences, and Invitae. D.C. received advisory board fees from Abbott, outside of this work. R.B.S. has received lecture fees and advisory board fees from BMS/Pfizer and Bayer outside this work. M.K. has received grants from Roche, Bayer, BMS, Boston Scientific, Daiichi Sankyo, Pfizer, Abbott, and Medtronic, as well as royalties from Springer Nature, outside of this work. M.R. reports consultancy fees from Bayer (OCEANIC-AF national PI), InCarda Therapeutics (RESTORE-SR national PI), Novartis to the institution, and speaker fee from Daiichi-Sankyo, Pfizer to the institution, all outside of this work. A.N. has served as consultant for Abbott, Biotronik, Biosense Webster, Boston Scientific, Field Medical, iRhythm, Medtronic and Pulse Bioscience. C.T.R. reports research grants through Brigham and Women’s Hospital from Anthos, AstraZeneca, Daiichi Sankyo, Janssen, and Novartis and has received honoraria for scientific advisory boards and consulting from Anthos, Bayer, Bristol Myers Squibb, Daiichi Sankyo, Janssen, and Pfizer. N.A.M, C.T.R, and M.S.S. are members of the TIMI (Thrombolysis in Myocardial Infarction) Study Group, which has received institutional research grant support through Brigham and Women’s Hospital from Abbott, Abiomed, Inc., Amgen, Anthos Therapeutics, ARCA Biopharma, Inc., AstraZeneca, Boehringer Ingelheim, Cleerly, Inc., Daiichi-Sankyo, Ionis Pharmaceuticals, Inc., Janssen Research and Development, LLC, MedImmune, Merck, Novartis, Pfizer, Regeneron Pharmaceuticals, Inc., Roche, Saghmos Therapeutics, Inc., Softcell Medical Limited, The Medicines Company, Verve Therapeutics, Inc., Zora Biosciences. S.M.D. previously received consulting fees from Tourmaline Bio and currently receives in kind research support from Novo Nordisk and Amgen. Supplementary Files AFsequencingfreeze2supplement.pdf Supplementary Materials AFsequencingfreeze2SupplementaryTables.xlsx Supplementary Tables 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. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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-9191644","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Biological Sciences - Article","associatedPublications":[],"authors":[{"id":613405732,"identity":"15bfbfcc-992e-4560-845c-bb920395774d","order_by":0,"name":"Sean 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and he has consulted for Bayer AG. S.A.L. is a full-time employee of Novartis Institutes of BioMedical Research as of July 18, 2022. S.A.L. previously received sponsored research support from Bristol Myers Squibb, Pfizer, Boehringer Ingelheim, Fitbit, Medtronic, Premier, and IBM, and has consulted for Bristol Myers Squibb, Pfizer, Blackstone Life Sciences, and Invitae. D.C. received advisory board fees from Abbott, outside of this work. R.B.S. has received lecture fees and advisory board fees from BMS/Pfizer and Bayer outside this work. M.K. has received grants from Roche, Bayer, BMS, Boston Scientific, Daiichi Sankyo, Pfizer, Abbott, and Medtronic, as well as royalties from Springer Nature, outside of this work. M.R. reports consultancy fees from Bayer (OCEANIC-AF national PI), InCarda Therapeutics (RESTORE-SR national PI), Novartis to the institution, and speaker fee from Daiichi-Sankyo, Pfizer to the institution, all outside of this work. A.N. has served as consultant for Abbott, Biotronik, Biosense Webster, Boston Scientific, Field Medical, iRhythm, Medtronic and Pulse Bioscience. C.T.R. reports research grants through Brigham and Women’s Hospital from Anthos, AstraZeneca, Daiichi Sankyo, Janssen, and Novartis and has received honoraria for scientific advisory boards and consulting from Anthos, Bayer, Bristol Myers Squibb, Daiichi Sankyo, Janssen, and Pfizer. N.A.M, C.T.R, and M.S.S. are members of the TIMI (Thrombolysis in Myocardial Infarction) Study Group, which has received institutional research grant support through Brigham and Women’s Hospital from Abbott, Abiomed, Inc., Amgen, Anthos Therapeutics, ARCA Biopharma, Inc., AstraZeneca, Boehringer Ingelheim, Cleerly, Inc., Daiichi-Sankyo, Ionis Pharmaceuticals, Inc., Janssen Research and Development, LLC, MedImmune, Merck, Novartis, Pfizer, Regeneron Pharmaceuticals, Inc., Roche, Saghmos Therapeutics, Inc., Softcell Medical Limited, The Medicines Company, Verve Therapeutics, Inc., Zora Biosciences. S.M.D. previously received consulting fees from Tourmaline Bio and currently receives in kind research support from Novo Nordisk and Amgen.","formattedTitle":"Rare coding variant architecture and gene discovery from 130,000 sequenced cases of atrial fibrillation","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-9191644/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9191644/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Rare coding genetic variants may exert large effects on risk of common disease, yet their contribution to disease architecture and their utility in gene prioritization remain limited by inadequate sample sizes. Here, we performed a massive-scale rare variant association study (RVAS), analyzing over 1.1 million sequenced participants among which 130,000 had atrial fibrillation (AF). Through a multi-mask burden testing approach, we identified 15 genes significantly associated with AF through rare large-effect variation. Integrative analyses revealed strong convergence between genes implicated by rare and common variation, and highlighted instances where RVAS data may aid in GWAS prioritization. Nevertheless, several RVAS genes were not among GWAS loci (\u003ci\u003eFAM189A2\u003c/i\u003e, \u003ci\u003eACTC1\u003c/i\u003e, \u003ci\u003eFNIP1\u003c/i\u003e, \u003ci\u003eFBN1\u003c/i\u003e), or were not nominated through contemporary GWAS prioritization (\u003ci\u003eKDM5B\u003c/i\u003e, \u003ci\u003eZFP36L2\u003c/i\u003e). Finally, we observed that ultra-rare protein-disrupting variants - concentrated in a small number of large-effect size genes - explained at least 2% of AF susceptibility across European and African ancestry groups. These findings refine the genetic architecture of AF, while highlighting the value and cost of RVAS for genomic discovery in common disease.","manuscriptTitle":"Rare coding variant architecture and gene discovery from 130,000 sequenced cases of atrial fibrillation","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-05-04 17:44:33","doi":"10.21203/rs.3.rs-9191644/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":"807fa242-7de2-4653-a21d-d4ab19936249","owner":[],"postedDate":"May 4th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":65275251,"name":"Biological sciences/Genetics/Genomics"},{"id":65275252,"name":"Biological sciences/Genetics/Genetic association study"},{"id":65275253,"name":"Health sciences/Diseases/Cardiovascular diseases/Arrhythmias/Atrial fibrillation"}],"tags":[],"updatedAt":"2026-05-04T17:44:34+00:00","versionOfRecord":[],"versionCreatedAt":"2026-05-04 17:44:33","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9191644","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9191644","identity":"rs-9191644","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}