Multi-ancestry Genome-wide Association Study of Inpatient Opioid Dosing Following Knee or Hip Arthroplasty

Multi-ancestry Genome-wide Association Study of Inpatient Opioid Dosing Following Knee or Hip Arthroplasty | 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 Multi-ancestry Genome-wide Association Study of Inpatient Opioid Dosing Following Knee or Hip Arthroplasty Henry Kranzler, Zeal Jinwala, Christal Davis, Jackson SooHoo, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7330342/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 Opioids are commonly prescribed to manage acute postoperative pain. However, individuals vary in their opioid dosing needs, with no validated biomarkers to guide prescribing. We used electronic health records (EHR) data from the Million Veteran Program sample to investigate individual differences in opioid analgesic dosing following knee (n=18,540) or hip (n=9,363) arthroplasty. We extracted data from pharmacy records on inpatient opioid medications to estimate average daily morphine milligram equivalent (MME) dosages and used genome-wide association studies (GWAS) to identify genetic variants associated with daily MME dosage, followed by a cross-ancestry and cross-phenotype meta-analysis. We identified two genome-wide significant loci in the African ancestry knee arthroplasty GWAS and three in the Admixed-American ancestry hip arthroplasty GWAS. Multiple other loci in African, Admixed-American, and European populations were nominally significant. The study provides a framework for the use of EHR data to examine the genetics of opioid dosing in post-operative care. Health sciences/Diseases/Psychiatric disorders/Addiction Biological sciences/Genetics/Genetic association study Figures Figure 1 Figure 2 Full Text Additional Declarations Yes there is potential conflict of interest. Tables 1 and 2 are available in the Supplementary Files section. Supplementary Files Table1.xlsx Table 1: Sample characteristics Table2.xlsx Table 2: Summary of SNPs reaching nominal significance (p < 5 x 10-6) in the cross-ancestry meta-analysis SupplementalInformation.docx Supplemental Information SupplementaryTables.xlsx Supplementary Tables SupplementaryFigures.docx Supplementary Figures 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. 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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-7330342","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":500030747,"identity":"0395f2d0-f1c9-4349-b72b-04194e4e741d","order_by":0,"name":"Henry Kranzler","email":"data:image/png;base64,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","orcid":"https://orcid.org/0000-0002-1018-0450","institution":"University of Pennsylvania Perelman School of Medicine","correspondingAuthor":true,"prefix":"","firstName":"Henry","middleName":"","lastName":"Kranzler","suffix":""},{"id":500030748,"identity":"05191576-2b63-4d5e-8f61-2910b2c76b6a","order_by":1,"name":"Zeal Jinwala","email":"","orcid":"https://orcid.org/0009-0005-5062-0827","institution":"Washington University in St. Louis","correspondingAuthor":false,"prefix":"","firstName":"Zeal","middleName":"","lastName":"Jinwala","suffix":""},{"id":500030749,"identity":"85a9359d-9120-419a-b94b-adab80cd62e7","order_by":2,"name":"Christal Davis","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Christal","middleName":"","lastName":"Davis","suffix":""},{"id":500030750,"identity":"f4529c86-734d-488f-83d3-dad250c946cd","order_by":3,"name":"Jackson SooHoo","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Jackson","middleName":"","lastName":"SooHoo","suffix":""},{"id":500030751,"identity":"4c217c33-bec3-4a5a-842f-69483f03d57c","order_by":4,"name":"Joel Gelernter","email":"","orcid":"https://orcid.org/0000-0002-4067-1859","institution":"Yale University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Joel","middleName":"","lastName":"Gelernter","suffix":""},{"id":500030752,"identity":"d456fd31-ce94-44fc-961f-ee86cdbb4efd","order_by":5,"name":"Rachel Kember","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Rachel","middleName":"","lastName":"Kember","suffix":""},{"id":500030753,"identity":"adc7249e-de69-44e8-9268-23694fdab8ed","order_by":6,"name":"Rachel Vickers-Smith","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Rachel","middleName":"","lastName":"Vickers-Smith","suffix":""}],"badges":[],"createdAt":"2025-08-08 22:20:15","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7330342/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7330342/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":89535704,"identity":"2113e187-1362-4a84-b24a-92b8a63def5e","added_by":"auto","created_at":"2025-08-21 05:10:19","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":56825,"visible":true,"origin":"","legend":"\u003cp\u003eSchematic of the phenotype workflow\u003c/p\u003e","description":"","filename":"Figure11.png","url":"https://assets-eu.researchsquare.com/files/rs-7330342/v1/2c6a205399a6c3e067245716.png"},{"id":89535717,"identity":"35a2b8f2-5b41-41a2-b42a-13a98775d94f","added_by":"auto","created_at":"2025-08-21 05:10:19","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":217412,"visible":true,"origin":"","legend":"\u003cp\u003eCross-ancestry and cross-phenotype genome-wide association results for estimated average MME opioid doses in who had a knee or hip arthroplasty. The Manhattan plot displays the –log₁₀(P) values of SNP associations across the genome. The red horizontal line indicates the genome-wide significance threshold (P = 5 × 10- 8 ), and the blue line marks the suggestive significance threshold (P = 1 × 10⁻6 ). SNPs exceeding the suggestive threshold are labeled with their rsIDs. The plot in the upper right corner shows the quantile– quantile (QQ) plot of observed versus expected P-values\u003c/p\u003e","description":"","filename":"Figure21.png","url":"https://assets-eu.researchsquare.com/files/rs-7330342/v1/b141fefa2d6f4a4f439deade.png"},{"id":90817089,"identity":"515650df-4623-4f42-b5e2-8f2ddfee9ee9","added_by":"auto","created_at":"2025-09-08 13:24:05","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":446019,"visible":true,"origin":"","legend":"Article File","description":"","filename":"manuscriptforsubmission.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7330342/v1_covered_5c71f824-9684-42a5-94fd-3b308ae342e9.pdf"},{"id":89535705,"identity":"4fd6edab-6523-4481-8a40-5dfc9deff3de","added_by":"auto","created_at":"2025-08-21 05:10:19","extension":"xlsx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":10432,"visible":true,"origin":"","legend":"Table 1: Sample characteristics","description":"","filename":"Table1.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-7330342/v1/e19ffb16634fd284a1bbdc07.xlsx"},{"id":89535718,"identity":"b1a6e73d-951d-406e-b548-41523bcf7115","added_by":"auto","created_at":"2025-08-21 05:10:19","extension":"xlsx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":10203,"visible":true,"origin":"","legend":"Table 2: Summary of SNPs reaching nominal significance (p \u0026lt; 5 x 10-6) in the cross-ancestry meta-analysis","description":"","filename":"Table2.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-7330342/v1/d8f7cf785871babfb2c936be.xlsx"},{"id":89537169,"identity":"40a170e9-0913-408e-b865-e5fab750c109","added_by":"auto","created_at":"2025-08-21 05:34:24","extension":"docx","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":24236,"visible":true,"origin":"","legend":"Supplemental Information","description":"","filename":"SupplementalInformation.docx","url":"https://assets-eu.researchsquare.com/files/rs-7330342/v1/9d6756a5aadcba766f24da3c.docx"},{"id":89535726,"identity":"29dd166d-dc25-497e-842f-a990c624c5aa","added_by":"auto","created_at":"2025-08-21 05:10:19","extension":"xlsx","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":614562,"visible":true,"origin":"","legend":"Supplementary Tables","description":"","filename":"SupplementaryTables.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-7330342/v1/513e3160cec31a7c7348465b.xlsx"},{"id":89535724,"identity":"e40243b0-6c90-43f7-a9cc-95f62663579a","added_by":"auto","created_at":"2025-08-21 05:10:19","extension":"docx","order_by":5,"title":"","display":"","copyAsset":false,"role":"supplement","size":7072246,"visible":true,"origin":"","legend":"Supplementary Figures","description":"","filename":"SupplementaryFigures.docx","url":"https://assets-eu.researchsquare.com/files/rs-7330342/v1/8fb6b8629db73cc1f6aa57e5.docx"}],"financialInterests":"\u003cp\u003e\u003cstrong\u003eYes\u003c/strong\u003e there is potential conflict of interest.\u003c/p\u003e\n\u003cp\u003eTables 1 and 2 are available in the Supplementary Files section.\u003c/p\u003e","formattedTitle":"Multi-ancestry Genome-wide Association Study of Inpatient Opioid Dosing Following Knee or Hip Arthroplasty","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"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":"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":"","lastPublishedDoi":"10.21203/rs.3.rs-7330342/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7330342/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Opioids are commonly prescribed to manage acute postoperative pain. However, individuals vary in their opioid dosing needs, with no validated biomarkers to guide prescribing. We used electronic health records (EHR) data from the Million Veteran Program sample to investigate individual differences in opioid analgesic dosing following knee (n=18,540) or hip (n=9,363) arthroplasty. We extracted data from pharmacy records on inpatient opioid medications to estimate average daily morphine milligram equivalent (MME) dosages and used genome-wide association studies (GWAS) to identify genetic variants associated with daily MME dosage, followed by a cross-ancestry and cross-phenotype meta-analysis. We identified two genome-wide significant loci in the African ancestry knee arthroplasty GWAS and three in the Admixed-American ancestry hip arthroplasty GWAS. Multiple other loci in African, Admixed-American, and European populations were nominally significant. 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