The LRRK2 p.L1795F variant causes Parkinson’s disease in the European population

The LRRK2 p.L1795F variant causes Parkinson’s disease in the European population | 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 The LRRK2 p.L1795F variant causes Parkinson’s disease in the European population Lara Lange, Kristin Levine, Susan Fox, Connie Marras, Nazish Ahmed, and 19 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4772543/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 25 Mar, 2025 Read the published version in npj Parkinson's Disease → Version 1 posted 11 You are reading this latest preprint version Abstract Pathogenic variants in the LRRK2 gene represent the most common cause of autosomal dominant Parkinson’s disease (PD) worldwide. We identified the LRRK2 p.L1795F variant in 14 White/European ancestry PD patients, including two families with multiple affected carriers and seven additional affected individuals with familial PD using genotyping and sequencing data from more than 50,000 individuals through GP2, AMP-PD, PDGENEration, and CENTOGENE. All variant carriers were of White/European ancestry, and those with available genotyping data shared a common haplotype. The clinical presentation of p.L1795F carriers resembles that of other LRRK2 pathogenic variant carriers. Combined with published functional evidence showing strongly enhanced LRRK2 kinase activity, our findings provide conclusive evidence that the LRRK2 p.L1795F variant is pathogenic. It represents a rare cause of PD in the European population but needs to be included in genetic testing efforts and considered for ongoing gene-specific clinical trials. Biological sciences/Genetics/Mutation Health sciences/Neurology/Neurological disorders/Parkinson's disease Full Text Additional Declarations (Not answered) Supplementary Files SupplementaryTables.pdf Cite Share Download PDF Status: Published Journal Publication published 25 Mar, 2025 Read the published version in npj Parkinson's Disease → Version 1 posted Editorial decision: revise 06 Sep, 2024 Review # 2 received at journal 02 Sep, 2024 Review # 3 received at journal 08 Aug, 2024 Reviewer # 3 agreed at journal 31 Jul, 2024 Reviewer # 2 agreed at journal 26 Jul, 2024 Review # 1 received at journal 26 Jul, 2024 Reviewer # 1 agreed at journal 26 Jul, 2024 Reviewers invited by journal 26 Jul, 2024 Editor assigned by journal 26 Jul, 2024 Submission checks completed at journal 23 Jul, 2024 First submitted to journal 20 Jul, 2024 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-4772543","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":337812771,"identity":"bead3270-ef9e-403a-9ae9-01dd03d6fc45","order_by":0,"name":"Lara Lange","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABCElEQVRIiWNgGAWjYBACPgYGxgMgBj8QH2AoYGAwYGBgZmBgw62FDawSCCQbQAwDUrQYQEhitLAfYDjwc0etnPGN3INAWw7LmbM3PzZgKLPBrYUngeFg75njxmY38hJAWowte44ZJzCcS8PjsASGA7xtxxK33cgxOPzH4HDihhs5zAcY2w7j1sL/gOHg37Zj9Ztn5BiAbKnfcP8NSMt/3FokEhgO87bVJBhIQLQkGNzgYU5gbDuAR8vDhsOybQcMZ5x5A9KSbrizJ83YIOFcMk4t/PzJBx++bauT52/PMf7AUGEtb85++LHEhzI7nFqAkd8AJNA9m4BHAxTUEVYyCkbBKBgFIxcAAAQtVjnmmethAAAAAElFTkSuQmCC","orcid":"https://orcid.org/0000-0002-7162-9821","institution":"University of Lübeck","correspondingAuthor":true,"prefix":"","firstName":"Lara","middleName":"","lastName":"Lange","suffix":""},{"id":337812772,"identity":"f048929d-531b-41c8-babd-3b7c96cefc7c","order_by":1,"name":"Kristin Levine","email":"","orcid":"https://orcid.org/0000-0002-5702-0980","institution":"Data Tecnica International","correspondingAuthor":false,"prefix":"","firstName":"Kristin","middleName":"","lastName":"Levine","suffix":""},{"id":337812773,"identity":"818a1ff4-3f76-44dc-b155-c9b760d7fd53","order_by":2,"name":"Susan Fox","email":"","orcid":"","institution":"Edmond J. Safra Program in Parkinson's Disease and the Morton and Gloria Shulman Movement Disorders Clinic, Toronto Western Hospital, University Health Network, University of Toronto, Toronto, Ontar","correspondingAuthor":false,"prefix":"","firstName":"Susan","middleName":"","lastName":"Fox","suffix":""},{"id":337812774,"identity":"0abc60cf-f06a-4a04-89c0-e33a5b287f34","order_by":3,"name":"Connie Marras","email":"","orcid":"","institution":"University of Toronto","correspondingAuthor":false,"prefix":"","firstName":"Connie","middleName":"","lastName":"Marras","suffix":""},{"id":337812775,"identity":"21c1bc17-80cd-4ec6-95c2-f59802ed1954","order_by":4,"name":"Nazish Ahmed","email":"","orcid":"","institution":"University Health Network","correspondingAuthor":false,"prefix":"","firstName":"Nazish","middleName":"","lastName":"Ahmed","suffix":""},{"id":337812776,"identity":"de2cbf9d-e895-420d-8320-3991f19df3fa","order_by":5,"name":"Nicole Kuznetsov","email":"","orcid":"","institution":"Center for Alzheimer's and Related Dementias (CARD), National Institute on Aging and National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA","correspondingAuthor":false,"prefix":"","firstName":"Nicole","middleName":"","lastName":"Kuznetsov","suffix":""},{"id":337812777,"identity":"2771a743-0192-4e9a-9d0e-f17890221470","order_by":6,"name":"Dan Vitale","email":"","orcid":"","institution":"Data Tecnica International LLC","correspondingAuthor":false,"prefix":"","firstName":"Dan","middleName":"","lastName":"Vitale","suffix":""},{"id":337812778,"identity":"6b40be2a-0bf0-4fb4-b481-f21464c7e6a6","order_by":7,"name":"Hirotaka Iwaki","email":"","orcid":"https://orcid.org/0000-0002-8982-7885","institution":"Data Tecnica International","correspondingAuthor":false,"prefix":"","firstName":"Hirotaka","middleName":"","lastName":"Iwaki","suffix":""},{"id":337812779,"identity":"b9c588e8-a8a8-4844-89ed-40b424742eaf","order_by":8,"name":"Katja Lohmann","email":"","orcid":"","institution":"Institute of Neurogenetics, University of Luebeck, Luebeck, Germany","correspondingAuthor":false,"prefix":"","firstName":"Katja","middleName":"","lastName":"Lohmann","suffix":""},{"id":337812780,"identity":"64583a2e-e0e0-4462-86e4-336ce722c3f4","order_by":9,"name":"Luca Marsili","email":"","orcid":"","institution":"University of Cincinnati, Cincinnati, Ohio, USA","correspondingAuthor":false,"prefix":"","firstName":"Luca","middleName":"","lastName":"Marsili","suffix":""},{"id":337812781,"identity":"2889d671-8440-4e7a-8ffa-d76bc2f3f428","order_by":10,"name":"Alberto Espay","email":"","orcid":"https://orcid.org/0000-0002-3389-136X","institution":"Gardner Family Center for Parkinson’s Disease and Movement Disorders, Department of Neurology, University of Cincinnati College of Medicine, Cincinnati, Ohio","correspondingAuthor":false,"prefix":"","firstName":"Alberto","middleName":"","lastName":"Espay","suffix":""},{"id":337812782,"identity":"9caa635b-c018-49d7-9c2b-762353b7ed8c","order_by":11,"name":"Peter Bauer","email":"","orcid":"","institution":"Centogene GmbH, Rostock, Germany","correspondingAuthor":false,"prefix":"","firstName":"Peter","middleName":"","lastName":"Bauer","suffix":""},{"id":337812783,"identity":"44ba767a-2608-40d4-96a5-a0aac0ff9626","order_by":12,"name":"Christian Beetz","email":"","orcid":"","institution":"CENTOGENE GmbH, Am Strande 7, 18055 Rostock, Germany","correspondingAuthor":false,"prefix":"","firstName":"Christian","middleName":"","lastName":"Beetz","suffix":""},{"id":337812784,"identity":"8990ed30-242a-4431-8dad-12f2c2e1963c","order_by":13,"name":"Jessica Martin","email":"","orcid":"https://orcid.org/0009-0000-0830-9289","institution":"Center for Alzheimer's and Related Dementias (CARD), National Institute on Aging and National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA","correspondingAuthor":false,"prefix":"","firstName":"Jessica","middleName":"","lastName":"Martin","suffix":""},{"id":337812785,"identity":"b4ae449a-48d6-44fc-a983-f041f4433d70","order_by":14,"name":"Stewart Factor","email":"","orcid":"https://orcid.org/0000-0002-0449-973X","institution":"Emory University","correspondingAuthor":false,"prefix":"","firstName":"Stewart","middleName":"","lastName":"Factor","suffix":""},{"id":337812786,"identity":"cae4aebf-d25d-4e72-aef3-0c40b106e9f4","order_by":15,"name":"Lenora Higginbotham","email":"","orcid":"","institution":"Emory","correspondingAuthor":false,"prefix":"","firstName":"Lenora","middleName":"","lastName":"Higginbotham","suffix":""},{"id":337812787,"identity":"b9c18c13-3cd5-4496-ad00-8fed1a304414","order_by":16,"name":"Honglei Chen","email":"","orcid":"","institution":"Michigan State University","correspondingAuthor":false,"prefix":"","firstName":"Honglei","middleName":"","lastName":"Chen","suffix":""},{"id":337812788,"identity":"0da6cdbb-65ac-472a-95fc-a590101620e8","order_by":17,"name":"Hampton Leonard","email":"","orcid":"","institution":"National Institute on Aging","correspondingAuthor":false,"prefix":"","firstName":"Hampton","middleName":"","lastName":"Leonard","suffix":""},{"id":337812789,"identity":"6515420e-98cb-40f9-8642-d8e7c7642665","order_by":18,"name":"Mike Nalls","email":"","orcid":"https://orcid.org/0000-0003-0319-4325","institution":"National Institute on Aging, National Institutes of Health","correspondingAuthor":false,"prefix":"","firstName":"Mike","middleName":"","lastName":"Nalls","suffix":""},{"id":337812790,"identity":"1602f6fa-114f-4de0-b138-1722389c75c6","order_by":19,"name":"Niccolo E. Mencacci","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Niccolo","middleName":"E.","lastName":"Mencacci","suffix":""},{"id":337812791,"identity":"607e2ac0-67bf-4a01-87d4-7461c862f27f","order_by":20,"name":"Huw Morris","email":"","orcid":"https://orcid.org/0000-0002-5473-3774","institution":"University College London","correspondingAuthor":false,"prefix":"","firstName":"Huw","middleName":"","lastName":"Morris","suffix":""},{"id":337812792,"identity":"d1298119-ee2e-4328-b3f8-d971ac946586","order_by":21,"name":"Christine Klein","email":"","orcid":"","institution":"Institute of Neurogenetics and Department of Neurology","correspondingAuthor":false,"prefix":"","firstName":"Christine","middleName":"","lastName":"Klein","suffix":""},{"id":337812793,"identity":"313f4ab7-49d8-4d03-8ae2-71e6952d193a","order_by":22,"name":"Cornelis Blauwendraat","email":"","orcid":"https://orcid.org/0000-0001-9358-8111","institution":"NIH","correspondingAuthor":false,"prefix":"","firstName":"Cornelis","middleName":"","lastName":"Blauwendraat","suffix":""},{"id":337812794,"identity":"e907a126-824e-4d10-b420-95cbee952e6d","order_by":23,"name":"Zih-Hua Fang","email":"","orcid":"https://orcid.org/0000-0002-0225-8772","institution":"German Center for Neurodegenerative Diseases (DZNE)","correspondingAuthor":false,"prefix":"","firstName":"Zih-Hua","middleName":"","lastName":"Fang","suffix":""}],"badges":[],"createdAt":"2024-07-20 10:00:09","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4772543/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4772543/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s41531-025-00896-2","type":"published","date":"2025-03-25T04:00:00+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":79246875,"identity":"fa3d9905-1313-4256-9c52-57b1a3de2aea","added_by":"auto","created_at":"2025-03-26 07:10:31","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1159535,"visible":true,"origin":"","legend":"","description":"","filename":"LangeTheLRRK2p.L1795FvariantcausesParkinsonXXXsdiseaseintheEuropeanpopulation.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4772543/v1_covered_2287d5c3-084a-416a-9a3a-8e5601f562e2.pdf"},{"id":64916337,"identity":"e530aedd-4fdc-4fc8-8e25-bf1edbab3981","added_by":"auto","created_at":"2024-09-20 10:51:02","extension":"pdf","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":3124850,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryTables.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4772543/v1/a5a7bdedca0d787a09fa7cb1.pdf"}],"financialInterests":"(Not answered)","formattedTitle":"The \u003ci\u003eLRRK2 p.L1795F\u003c/i\u003e variant causes Parkinson’s disease in the European\r\npopulation","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"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":"npj-parkinsons-disease","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"npjparkd","sideBox":"Learn more about [npj Parkinson's Disease](http://www.nature.com/npjparkd/)","snPcode":"41531","submissionUrl":"https://submission.springernature.com/new-submission/41531/3","title":"npj Parkinson's Disease","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"NPJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-4772543/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4772543/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Pathogenic variants in the \u003ci\u003eLRRK2\u003c/i\u003e gene represent the most common cause of autosomal\r\ndominant Parkinson’s disease (PD) worldwide. We identified the \u003ci\u003eLRRK2\u003c/i\u003e p.L1795F variant in\r\n14 White/European ancestry PD patients, including two families with multiple affected carriers\r\nand seven additional affected individuals with familial PD using genotyping and sequencing\r\ndata from more than 50,000 individuals through GP2, AMP-PD, PDGENEration, and\r\nCENTOGENE. All variant carriers were of White/European ancestry, and those with available\r\ngenotyping data shared a common haplotype. The clinical presentation of p.L1795F carriers\r\nresembles that of other \u003ci\u003eLRRK2\u003c/i\u003e pathogenic variant carriers. Combined with published\r\nfunctional evidence showing strongly enhanced LRRK2 kinase activity, our findings provide\r\nconclusive evidence that the \u003ci\u003eLRRK2\u003c/i\u003e p.L1795F variant is pathogenic. It represents a rare\r\ncause of PD in the European population but needs to be included in genetic testing efforts and\r\nconsidered for ongoing gene-specific clinical trials.","manuscriptTitle":"The LRRK2 p.L1795F variant causes Parkinson’s disease in the European\npopulation","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-09-20 10:50:57","doi":"10.21203/rs.3.rs-4772543/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"revise","date":"2024-09-06T10:29:12+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"This content is not available.","date":"2024-09-02T23:16:48+00:00","index":2,"fulltext":"This content is not available."},{"type":"editorInvitedReview","content":"This content is not available.","date":"2024-08-08T17:07:32+00:00","index":3,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2024-07-31T19:13:22+00:00","index":3,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2024-07-26T18:41:51+00:00","index":2,"fulltext":"This content is not available."},{"type":"editorInvitedReview","content":"This content is not available.","date":"2024-07-26T15:01:17+00:00","index":1,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2024-07-26T13:03:12+00:00","index":1,"fulltext":"This content is not available."},{"type":"reviewersInvited","content":"","date":"2024-07-26T12:49:16+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-07-26T12:17:01+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-07-23T05:16:40+00:00","index":"","fulltext":""},{"type":"submitted","content":"npj Parkinson's Disease","date":"2024-07-20T09:55:29+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"npj-parkinsons-disease","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"npjparkd","sideBox":"Learn more about [npj Parkinson's Disease](http://www.nature.com/npjparkd/)","snPcode":"41531","submissionUrl":"https://submission.springernature.com/new-submission/41531/3","title":"npj Parkinson's Disease","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"NPJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"46fd7921-26fc-401f-8096-b156fb0e4c44","owner":[],"postedDate":"September 20th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":35785863,"name":"Biological sciences/Genetics/Mutation"},{"id":35785864,"name":"Health sciences/Neurology/Neurological disorders/Parkinson's disease"}],"tags":[],"updatedAt":"2025-03-26T07:10:21+00:00","versionOfRecord":{"articleIdentity":"rs-4772543","link":"https://doi.org/10.1038/s41531-025-00896-2","journal":{"identity":"npj-parkinsons-disease","isVorOnly":false,"title":"npj Parkinson's Disease"},"publishedOn":"2025-03-25 04:00:00","publishedOnDateReadable":"March 25th, 2025"},"versionCreatedAt":"2024-09-20 10:50:57","video":"","vorDoi":"10.1038/s41531-025-00896-2","vorDoiUrl":"https://doi.org/10.1038/s41531-025-00896-2","workflowStages":[]},"version":"v1","identity":"rs-4772543","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4772543","identity":"rs-4772543","version":["v1"]},"buildId":"_2-kVJe1T_tPrBINL-cwx","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}