ArticleAnnals of neurology2021
Genomewide Association Studies of LRRK2 Modifiers of Parkinson's Disease.
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Article in Annals of neurology, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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Who cites it
26 citing papers in PubMed, 47 citations in OpenAlex.
- Lysosomal dysfunction in neurodegenerative disease.Nature reviews. Neurology · 2026Review
- Individualized Bayesian Inference Identifies Novel Genetic Variants for Parkinson's Disease.Genetic epidemiology · 2026Article
- CORO1C (coronin 1C) promotes autophagosome formation by coordinating branched actin network dynamics.Autophagy · 2026Article
- Mitochondrial resilience: a convergent framework for pathogenesis and neuroprotection in Parkinson's disease.Frontiers in pharmacology · 2026Review
- Integrating rare and common variation in epilepsy genetics: from genetic architecture to penetrance and clinical expressivity.Frontiers in genetics · 2026Review
- Low-frequency genetic variants in GAK enhance Golgi function and protect against Parkinson's disease.medRxiv : the preprint server for health sciences · 2025Article
- Linking Parkinson's disease and melanoma: the impact of copper-driven cuproptosis and related mechanisms.NPJ Parkinson's disease · 2025Article
- Updated MDSGene review on the clinical and genetic spectrum of LRRK2 variants in Parkinson´s disease.NPJ Parkinson's disease · 2025Article
- TheResearch square · 2024Article
- Relevance of genetic testing in the gene-targeted trial era: the Rostock Parkinson's disease study.Brain : a journal of neurology · 2024Observational
- Mitophagy and cGAS-STING crosstalk in neuroinflammation.Acta pharmaceutica Sinica. B · 2024Review
- High-depth whole-genome sequencing identifies structure variants, copy number variants and short tandem repeats associated with Parkinson's disease.NPJ Parkinson's disease · 2024Article
- The Evolution of Genetic Variability at theGenes · 2024Article
- Identification of 27 allele-specific regulatory variants in Parkinson's disease using a massively parallel reporter assay.NPJ Parkinson's disease · 2024Article
- Genome-wide case-only analysis of gene-gene interactions with known Parkinson's disease risk variants reveals link between LRRK2 and SYT10.NPJ Parkinson's disease · 2023Article
- Circular RNAs in Parkinson's Disease: Reliable Biological Markers and Targets for Rehabilitation.Molecular neurobiology · 2023Article
- LRRK2 and Parkinson's disease: from genetics to targeted therapy.Annals of clinical and translational neurology · 2023Review
- Who is at Risk of Parkinson Disease? Refining the Preclinical Phase of GBA1 and LRRK2 Variant Carriers: a Clinical, Biochemical, and Imaging Approach.Current neurology and neuroscience reports · 2023Review
- Genetic modifiers of synucleinopathies-lessons from experimental models.Oxford open neuroscience · 2023Review
- Inflammation and immune dysfunction in Parkinson disease.Nature reviews. Immunology · 2022Review
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Authors and funding
62 authors at 20 institutions in 10 countries.
Dongbing Lai *Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN.ORCID 0000-0001-7803-580X
Babak Alipanahi *23andMe, Inc., Sunnyvale, CA.
Pierre Fontanillas *23andMe, Inc., Sunnyvale, CA.
Tae-Hwi Schwantes-AnDepartment of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN.
Jan AaslyDepartment of Neurology, St. Olavs Hospital, Trondheim, Norway.
Roy N AlcalayDepartment of Neurology, Columbia University, New York, NY.
Gary W BeechamJohn P. Hussman Institute for Human Genomics and Dr. John T. Macdonald Department of Human Genetics, University of Miami, Miller School of Medicine, Miami, FL.
Daniela BergDepartment of Neurology, Christian-Albrechts-University of Kiel, Kiel, Germany.
Susan BressmanDepartment of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY.
Alexis BriceSorbonne Université, Institut du Cerveau et de la Moelle épinière (ICM), AP-HP, Inserm, CNRS, University Hospital Pitié-Salpêtrière, Paris, France.
Kathrin BrockmanDepartment of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.ORCID 0000-0002-7515-8596
Lorraine ClarkDepartment of Pathology and Cell Biology, Columbia University, New York, NY.
Mark CooksonLaboratory of Neurogenetics, National Institute of Aging, National Institute of Health, Bethesda, MD.
Sayantan Das23andMe, Inc., Sunnyvale, CA.
Vivianna Van DeerlinDepartment of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA.
Jordan FollettLaboratory of Neurogenetics and Neuroscience, Fixel Institute for Neurological Diseases, McKnight Brain Institute, L5-101D, UF Clinical and Translational Science Institute, University of Florida, Gainesville, FL.
Matthew J FarrerLaboratory of Neurogenetics and Neuroscience, Fixel Institute for Neurological Diseases, McKnight Brain Institute, L5-101D, UF Clinical and Translational Science Institute, University of Florida, Gainesville, FL.
Joanne TrinhInstitute of Neurogenetics, University of Luebeck, Luebeck, Germany.
Thomas GasserDepartment of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
Stefano GoldwurmParkinson Institute, ASST "G.Pini-CTO, Milan, Italy.
Emil GustavssonCentre for Applied Neurogenetics, University of British Columbia, Vancouver, Canada.
Christine KleinInstitute of Neurogenetics, University of Luebeck, Luebeck, Germany.ORCID 0000-0003-2102-3431
Anthony E LangThe Edmond J. Safra Program in Parkinson's Disease and the Morton and Gloria Shulman Movement Disorders Clinic, Toronto Western Hospital, Toronto, Canada.
J William LangstonDepartments of Neurology, Neuroscience, and Pathology, Stanford University School of Medicine, Stanford, CA.
Jeanne LatourelleGNS Healthcare, Cambridge, MA.
Timothy LynchDublin Neurological Institute at the Mater Misericordiae University Hospital, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland.
Karen MarderDepartment of Neurology and Psychiatry, Taub Institute and Sergievsky Center, Columbia University Vagelos College of Physicians and Surgeons, New York, NY.
Connie MarrasThe Edmond J. Safra Program in Parkinson's Disease and the Morton and Gloria Shulman Movement Disorders Clinic, Toronto Western Hospital, Toronto, Canada.
Eden R MartinJohn P. Hussman Institute for Human Genomics and Dr. John T. Macdonald Department of Human Genetics, University of Miami, Miller School of Medicine, Miami, FL.
Cory Y McLean23andMe, Inc., Sunnyvale, CA.
Helen Mejia-SantanaGertrude H. Sergievsky Center, Columbia University, New York, NY.
Eric MolhoDepartment of Neurology, Albany Medical College, Albany, NY.
Richard H MyersDepartment of Neurology, Boston University, Boston, MA.
Karen NuytemansJohn P. Hussman Institute for Human Genomics and Dr. John T. Macdonald Department of Human Genetics, University of Miami, Miller School of Medicine, Miami, FL.
Laurie OzeliusDepartment of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY.
Haydeh PayamiDepartment of Neurology, University of Alabama at Birmingham, Birmingham, AL.
Deborah RaymondDepartment of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY.
Ekaterina RogaevaTanz Centre for Research in Neurodegenerative Diseases and Department of Neurology, University of Toronto, Toronto, Canada.
Michael P RogersDepartment of General Surgery, University of South Florida Morsani College of Medicine, Tampa, FL.
Owen A RossDepartments of Neuroscience and Clinical Genomics, Mayo Clinic, Jacksonville, FL.ORCID 0000-0003-4813-756X
Ali SamiiVA Puget Sound Health Care System and Department of Neurology, University of Washington, Seattle, WA.
Rachel Saunders-PullmanDepartment of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY.
Birgitt SchüleDepartment of Pathology, Stanford University School of Medicine, Stanford, CA.
Claudia SchulteDepartment of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
William K ScottJohn P. Hussman Institute for Human Genomics and Dr. John T. Macdonald Department of Human Genetics, University of Miami, Miller School of Medicine, Miami, FL.
Caroline TannerUniversity of California, San Francisco Veterans Affairs Health Care System, San Francisco, CA.
Eduardo TolosaParkinson Disease and Movement Disorders Unit, Hospital Clínic Universitari, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona (UB), Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Barcelona, Spain.
James E TomkinsSchool of Pharmacy, University of Reading, Reading, UK.
Dolores VilasParkinson Disease and Movement Disorders Unit, Hospital Clínic Universitari, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona (UB), Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Barcelona, Spain.
John Q TrojanowskiDepartment of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA.
23andMe Research Team23andMe, Inc., Sunnyvale, CA.
Ryan UittiDepartment of Neurology, Mayo Clinic, Jacksonville, FL.
Jeffery M VanceJohn P. Hussman Institute for Human Genomics and Dr. John T. Macdonald Department of Human Genetics, University of Miami, Miller School of Medicine, Miami, FL.
Naomi P VisanjiThe Edmond J. Safra Program in Parkinson's Disease and the Morton and Gloria Shulman Movement Disorders Clinic, Toronto Western Hospital, Toronto, Canada.ORCID 0000-0001-5968-7845
Zbigniew K WszolekDepartment of Neurology, Mayo Clinic, Jacksonville, FL.
Cyrus P ZabetianVA Puget Sound Health Care System and Department of Neurology, University of Washington, Seattle, WA.ORCID 0000-0002-7739-4306
Anat MirelmanTel Aviv Sourasky Medical Center, Sackler Faculty of Medicine and Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel.ORCID 0000-0002-1520-2292
Nir GiladiTel Aviv Sourasky Medical Center, Sackler Faculty of Medicine and Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel.
Avi Orr UrtregerTel Aviv Sourasky Medical Center, Sackler Faculty of Medicine and Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel.
Paul Cannon23andMe, Inc., Sunnyvale, CA.
Brian FiskeThe Michael J. Fox Foundation for Parkinson's Research, New York, NY.
Tatiana ForoudDepartment of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN.
University of Miami · USIcahn School of Medicine at Mount Sinai · US23andMe (United States) · USColumbia University · USGerman Center for Neurodegenerative Diseases · DEIndiana University School of MedicineTel Aviv University · ILToronto Western Hospital · CABiomedical Research Networking Center on Neurodegenerative Diseases · ESGoogle (United States) · USJacksonville College · USUniversity College Dublin · IEUniversity of Florida · USUniversity of Lübeck · DEUniversity of Pennsylvania · USUniversity of Washington · USAlbany Medical Center Hospital · USBoston University · USCentre National de la Recherche Scientifique · FRChristian-Albrechts-Universität zu Kiel · DE
Funding
Clinical and Translational Science AwardUL1TR001873 · NCATS · COLUMBIA UNIVERSITY HEALTH SCIENCES · PI REILLY, MUREDACH P · 2016 to 2025
$99.0MUPenn ADCC Biomarker CoreP30AG010124 · NIA · UNIVERSITY OF PENNSYLVANIA · PI XIE, SHARON XIANGWEN · 1991 to 2020
$35.1MClinical and Translational Science AwardUL1TR000040 · NCATS · COLUMBIA UNIVERSITY HEALTH SCIENCES · PI GINSBERG, HENRY N · 2012 to 2015
$26.2MProject IV: "Alpha-Synuclein Strains & Diverse Synucleinopathies"P50NS053488 · NINDS · UNIVERSITY OF PENNSYLVANIA · PI TROJANOWSKI, JOHN Q. · 2007 to 2017
$20.9MUdall Center Director's meeting poster awardP50NS062684 · NINDS · UNIVERSITY OF WASHINGTON · PI MONTINE, THOMAS J · 2009 to 2020
$18.3MLeucine rich repeat kinase 2 and dominantly inherited Parkinson diseaseZIAAG000948 · NIA · NATIONAL INSTITUTE ON AGING · PI COOKSON, MARK · 2009 to 2025
$18.3MProject IV "Tackling Heterogeneity of Cognitive Trajectory in LBD"U19AG062418 · NIA · UNIVERSITY OF PENNSYLVANIA · PI TROJANOWSKI, JOHN Q. · 2019 to 2023
$18.1MTHE GENETICS OF PARKINSONISMP50NS039764 · NINDS · UNIVERSITY OF MIAMI SCHOOL OF MEDICINE · PI VANCE, JEFFERY MARVIN · 1999 to 2010
$15.6MUtilization of proteomics and lipidomics to identify modifiers of LBDU54NS110435 · NINDS · MAYO CLINIC JACKSONVILLE · PI MCLEAN, PAMELA J · 2019 to 2023
$14.5MVitamin D Concentration, Genetic Modifiers, and Parkinson DiseaseP50NS071674 · NINDS · UNIVERSITY OF MIAMI SCHOOL OF MEDICINE · PI VANCE, JEFFERY MARVIN · 2010 to 2015
$10.2MNeuropathology CoreP50NS072187 · NINDS · MAYO CLINIC JACKSONVILLE · PI DICKSON, DENNIS WILLIAM · 2010 to 2017
$8.7MGENETIC EPIDEMIOLOGY OF PARKINSONS DISEASER01NS036630 · NINDS · COLUMBIA UNIVERSITY HEALTH SCIENCES · PI MARDER, KAREN S · 1998 to 2008
$6.8MBAND3 (Michael J Fox Foundation, Alzheimer's Association, Alzheimer's Research UK and Weston Brain Institute) 18063CSRD VA I01 CX001702Deutsche Forschungsgemeinschaft (DFG) FOR2488DOD W81XWH-17-1-0249Else Kroener Fresenius FoundationNational Institutes of Health (NIH) AG010124National Institutes of Health (NIH) AG062418National Institutes of Health (NIH) K02NS080915National Institutes of Health (NIH) NS036630National Institutes of Health (NIH) NS053488National Institutes of Health (NIH) R01NS096740National Institutes of Health (NIH) UL1TR001873NCATS NIH HHS UL1 TR000040NCATS NIH HHS UL1 TR001873NHLBI NIH HHS HHSN268201200008CNHLBI NIH HHS HHSN268201200008INIA NIH HHS P30 AG010124NIA NIH HHS U19 AG062418NINDS NIH HHS K02 NS080915NINDS NIH HHS NS071674NINDS NIH HHS P50 NS039764NINDS NIH HHS P50 NS053488NINDS NIH HHS P50 NS062684NINDS NIH HHS P50 NS071674NINDS NIH HHS P50 NS072187NINDS NIH HHS R01 NS036630NINDS NIH HHS R01 NS065070NINDS NIH HHS R01 NS078086NINDS NIH HHS R01-NS078086NINDS NIH HHS R01 NS096740NINDS NIH HHS R56 NS036630NINDS NIH HHS U01 NS107016NINDS NIH HHS U54 NS100693NINDS NIH HHS U54-NS100693NINDS NIH HHS U54 NS110435NINDS NIH HHS U54-NS110435the 2019 Biomarkers Across Neurodegenerative Diseases Grant ProgramThe Albertson Parkinson's Research FoundationThe Brookdale FoundationThe Canadian Consortium on Neurodegeneration in AgingThe Canadian Institutes of Health ResearchThe Department of Veterans Affairs 5I01CX001702The Functional Genomics of LBD ProgramThe Haworth Family Professorship in Neurodegenerative Diseases fundThe Little Family FoundationThe Mangurian Foundation Lewy Body Dementia Program at Mayo Clinic and Mayo Clinic Center for Individualized MedicineThe Michael J. Fox Foundation for Parkinson's Research Grants 7984The Michael J. Fox Foundation for Parkinson's Research Grants 7984.01The Michael J. Fox Foundation for Parkinson's Research Grants 7984.02The Michael J. Fox Foundation for Parkinson's Research Grants 8981The Parkinson's FoundationThe Riley Chair in Parkinson's DiseaseThe Sol Goldman Charitable Trust
Abstract
objectiveThe aim of this study was to search for genes/variants that modify the effect of LRRK2 mutations in terms of penetrance and age-at-onset of Parkinson's disease.
methodsWe performed the first genomewide association study of penetrance and age-at-onset of Parkinson's disease in LRRK2 mutation carriers (776 cases and 1,103 non-cases at their last evaluation). Cox proportional hazard models and linear mixed models were used to identify modifiers of penetrance and age-at-onset of LRRK2 mutations, respectively. We also investigated whether a polygenic risk score derived from a published genomewide association study of Parkinson's disease was able to explain variability in penetrance and age-at-onset in LRRK2 mutation carriers.
resultsA variant located in the intronic region of CORO1C on chromosome 12 (rs77395454; p value = 2.5E-08, beta = 1.27, SE = 0.23, risk allele: C) met genomewide significance for the penetrance model. Co-immunoprecipitation analyses of LRRK2 and CORO1C supported an interaction between these 2 proteins. A region on chromosome 3, within a previously reported linkage peak for Parkinson's disease susceptibility, showed suggestive associations in both models (penetrance top variant: p value = 1.1E-07; age-at-onset top variant: p value = 9.3E-07). A polygenic risk score derived from publicly available Parkinson's disease summary statistics was a significant predictor of penetrance, but not of age-at-onset.
interpretationThis study suggests that variants within or near CORO1C may modify the penetrance of LRRK2 mutations. In addition, common Parkinson's disease associated variants collectively increase the penetrance of LRRK2 mutations. ANN NEUROL 2021;90:82-94.
Indexed as
AgedFemaleGenetic Predisposition to DiseaseGenome-Wide Association StudyGenotypeHumansLeucine-Rich Repeat Serine-Threonine Protein Kinase-2MaleMiddle AgedMutationParkinson DiseasePenetranceLeucine-Rich Repeat Serine-Threonine Protein Kinase-2
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