Insights into Pathophysiological Pathways in ME/CFS Through Genetic Correlation and Mendelian Randomization

Insights into Pathophysiological Pathways in ME/CFS Through Genetic Correlation and Mendelian Randomization | 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 Short Report Insights into Pathophysiological Pathways in ME/CFS Through Genetic Correlation and Mendelian Randomization Matthias Wielscher, Leonardo Vincenzi, Wolfgang P Weninger, Eva S Schernhammer This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9363637/v2 This work is licensed under a CC BY 4.0 License Status: Posted Version 2 posted You are reading this latest preprint version Show more versions Abstract Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and post-acute infection syndromes (PAIS) are multisystem disorders involving immune, vascular, neuroinflammatory, and metabolic abnormalities, yet the causal relevance of these processes remains unclear. Using genome-wide summary statistics from DecodeME (15,579 cases), we performed genetic correlation, pleiotropic heritability, and Mendelian randomization analyses. Across 22 auxiliary traits spanning five mechanistic domains, cellular energetics, neurovascular regulation, and barrier–microbiome function showed the strongest genetic overlap with ME/CFS, with migraine and irritable bowel syndrome contributing most to shared pleiotropy. Immunothrombotic related and inflammatory traits showed smaller but measurable genetic correlations. Energetics-related traits, including type 2 diabetes and blood lactate, displayed consistent genetic correlation but relatively low shared pleiotropy, suggesting that metabolic dysfunction may act through broader physiological networks. Mendelian randomization identified three biomarkers with evidence for causal effects on ME/CFS risk: higher mitochondrial DNA copy number was protective, whereas increased glycoprotein acetyls and mean platelet volume increased risk. Together, these findings indicate that ME/CFS susceptibility reflects interacting pathways involving barrier–microbiome dysfunction, neurovascular instability, inflammation, platelet activation, and impaired cellular energetics Main Text Molecular Epidemiology Biostatistics Population Genetics Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) genetic correlation pleiotropy Mendelian randomization post-acute infection syndromes Full Text Additional Declarations The authors declare no competing interests. Cite Share Download PDF Status: Posted Version 2 posted You are reading this latest preprint version Show more versions 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-9363637","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Short Report","associatedPublications":[],"authors":[{"id":620660596,"identity":"a633fd04-a38b-4e6a-ad43-cb3709eac900","order_by":0,"name":"Matthias Wielscher","email":"data:image/png;base64,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","orcid":"https://orcid.org/0000-0003-4138-1383","institution":"Medical University of Vienna","correspondingAuthor":true,"prefix":"","firstName":"Matthias","middleName":"","lastName":"Wielscher","suffix":""},{"id":620660597,"identity":"ff718e90-84bd-4ad1-be8b-5834857720a4","order_by":1,"name":"Leonardo Vincenzi","email":"","orcid":"https://orcid.org/0009-0009-9116-349X","institution":"Medical University of Vienna","correspondingAuthor":false,"prefix":"","firstName":"Leonardo","middleName":"","lastName":"Vincenzi","suffix":""},{"id":620660598,"identity":"59fad4ad-d76e-4920-9afa-0349963bd3b4","order_by":2,"name":"Wolfgang P Weninger","email":"","orcid":"","institution":"Medical University of Vienna","correspondingAuthor":false,"prefix":"","firstName":"Wolfgang","middleName":"P","lastName":"Weninger","suffix":""},{"id":620660599,"identity":"81fc1ac4-4978-4f78-8e40-74d1332d2a5e","order_by":3,"name":"Eva S Schernhammer","email":"","orcid":"https://orcid.org/0000-0002-4337-9415","institution":"Medical University of Vienna","correspondingAuthor":false,"prefix":"","firstName":"Eva","middleName":"S","lastName":"Schernhammer","suffix":""}],"badges":[],"createdAt":"2026-04-09 05:50:55","currentVersionCode":2,"declarations":{"humanSubjects":true,"vertebrateSubjects":false,"conflictsOfInterestStatement":false,"humanSubjectEthicalGuidelines":true,"humanSubjectConsent":true,"humanSubjectClinicalTrial":false,"humanSubjectCaseReport":false,"vertebrateSubjectEthicalGuidelines":false},"doi":"10.21203/rs.3.rs-9363637/v2","doiUrl":"https://doi.org/10.21203/rs.3.rs-9363637/v2","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":107868270,"identity":"3eee5575-92e2-4b6f-a72e-7d5b66b2ccd8","added_by":"auto","created_at":"2026-04-27 07:09:46","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":703459,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript20260416.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9363637/v2_covered_d33833c6-7358-45d2-af2d-24317c5e3cd6.pdf"}],"financialInterests":"The authors declare no competing interests.","formattedTitle":"Insights into Pathophysiological Pathways in ME/CFS Through Genetic Correlation and Mendelian Randomization","fulltext":[],"fulltextSource":"","fullText":"","funders":[{"identity":"307c736a-d041-4a89-b4a9-640e43e306fb","identifier":"10.13039/501100001821","name":"Vienna Science and Technology Fund","awardNumber":"ME-CFS24-002","order_by":0}],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"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":"Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), genetic correlation, pleiotropy, Mendelian randomization, post-acute infection syndromes","lastPublishedDoi":"10.21203/rs.3.rs-9363637/v2","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9363637/v2","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eMyalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and post-acute infection syndromes (PAIS) are multisystem disorders involving immune, vascular, neuroinflammatory, and metabolic abnormalities, yet the causal relevance of these processes remains unclear. Using genome-wide summary statistics from DecodeME (15,579 cases), we performed genetic correlation, pleiotropic heritability, and Mendelian randomization analyses.\u003c/p\u003e \u003cp\u003eAcross 22 auxiliary traits spanning five mechanistic domains, cellular energetics, neurovascular regulation, and barrier\u0026ndash;microbiome function showed the strongest genetic overlap with ME/CFS, with migraine and irritable bowel syndrome contributing most to shared pleiotropy. Immunothrombotic related and inflammatory traits showed smaller but measurable genetic correlations. Energetics-related traits, including type 2 diabetes and blood lactate, displayed consistent genetic correlation but relatively low shared pleiotropy, suggesting that metabolic dysfunction may act through broader physiological networks.\u003c/p\u003e \u003cp\u003eMendelian randomization identified three biomarkers with evidence for causal effects on ME/CFS risk: higher mitochondrial DNA copy number was protective, whereas increased glycoprotein acetyls and mean platelet volume increased risk. Together, these findings indicate that ME/CFS susceptibility reflects interacting pathways involving barrier\u0026ndash;microbiome dysfunction, neurovascular instability, inflammation, platelet activation, and impaired cellular energetics\u003c/p\u003e \u003cp\u003eMain Text\u003c/p\u003e","manuscriptTitle":"Insights into Pathophysiological Pathways in ME/CFS Through Genetic Correlation and Mendelian Randomization","msid":"","msnumber":"","nonDraftVersions":[{"code":2,"date":"2026-04-21 17:43:28","doi":"10.21203/rs.3.rs-9363637/v2","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","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}},{"code":1,"date":"2026-04-10 04:04:09","doi":"10.21203/rs.3.rs-9363637/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","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}}],"origin":"","ownerIdentity":"6fd58030-9ffd-46ac-9c69-5a952216e0a9","owner":[],"postedDate":"April 21st, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":66052890,"name":"Molecular Epidemiology"},{"id":66052891,"name":"Biostatistics"},{"id":66052892,"name":"Population Genetics"}],"tags":[],"updatedAt":"2026-04-10T04:04:09+00:00","versionOfRecord":[],"versionCreatedAt":"2026-04-21 17:43:28","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v2","identity":"rs-9363637","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9363637","identity":"rs-9363637","version":["v2"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}