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dc.contributor.authorIwaki, Hirotaka
dc.contributor.authorBlauwendraat, Cornelis
dc.contributor.authorLeonard, Hampton L
dc.contributor.authorKim, Jonggeol J
dc.contributor.authorLiu, Ganqiang
dc.contributor.authorMaple-Grødem, Jodi
dc.contributor.authorCorvol, Jean-Christophe
dc.contributor.authorPihlstrøm, Lasse
dc.contributor.authorvan Nimwegen, Marlies
dc.contributor.authorHutten, Samantha J
dc.contributor.authorNguyen, Khanh-Dung H
dc.contributor.authorRick, Jacqueline
dc.contributor.authorEberly, Shirley
dc.contributor.authorFaghri, Faraz
dc.contributor.authorAuinger, Peggy
dc.contributor.authorScott, Kirsten M
dc.contributor.authorWijeyekoon, Ruwani
dc.contributor.authorVan Deerlin, Vivianna M
dc.contributor.authorHernandez, Dena G
dc.contributor.authorGibbs, J Raphael
dc.contributor.authorInternational Parkinson's Disease Genomics Consortium
dc.contributor.authorChitrala, Kumaraswamy Naidu
dc.contributor.authorDay-Williams, Aaron G
dc.contributor.authorBrice, Alexis
dc.contributor.authorAlves, Guido
dc.contributor.authorNoyce, Alastair J
dc.contributor.authorTysnes, Ole-Bjørn
dc.contributor.authorEvans, Jonathan R
dc.contributor.authorBreen, David P
dc.contributor.authorEstrada, Karol
dc.contributor.authorWegel, Claire E
dc.contributor.authorDanjou, Fabrice
dc.contributor.authorSimon, David K
dc.contributor.authorAndreassen, Ole
dc.contributor.authorRavina, Bernard
dc.contributor.authorToft, Mathias
dc.contributor.authorHeutink, Peter
dc.contributor.authorBloem, Bastiaan R
dc.contributor.authorWeintraub, Daniel
dc.contributor.authorBarker, Roger A
dc.contributor.authorWilliams-Gray, Caroline H
dc.contributor.authorvan de Warrenburg, Bart P
dc.contributor.authorVan Hilten, Jacobus J
dc.contributor.authorScherzer, Clemens R
dc.contributor.authorSingleton, Andrew B
dc.contributor.authorNalls, Mike A
dc.date.accessioned2019-07-29T12:22:23Z
dc.date.available2019-07-29T12:22:23Z
dc.date.issued2019-12
dc.identifier.issn0885-3185
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/295021
dc.description.abstractBACKGROUND: Several reports have identified different patterns of Parkinson's disease progression in individuals carrying missense variants in GBA or LRRK2 genes. The overall contribution of genetic factors to the severity and progression of Parkinson's disease, however, has not been well studied. OBJECTIVES: To test the association between genetic variants and the clinical features of Parkinson's disease on a genomewide scale. METHODS: We accumulated individual data from 12 longitudinal cohorts in a total of 4093 patients with 22,307 observations for a median of 3.81 years. Genomewide associations were evaluated for 25 cross-sectional and longitudinal phenotypes. Specific variants of interest, including 90 recently identified disease-risk variants, were also investigated post hoc for candidate associations with these phenotypes. RESULTS: Two variants were genomewide significant. Rs382940(T>A), within the intron of SLC44A1, was associated with reaching Hoehn and Yahr stage 3 or higher faster (hazard ratio 2.04 [1.58-2.62]; P value = 3.46E-8). Rs61863020(G>A), an intergenic variant and expression quantitative trait loci for α-2A adrenergic receptor, was associated with a lower prevalence of insomnia at baseline (odds ratio 0.63 [0.52-0.75]; P value = 4.74E-8). In the targeted analysis, we found 9 associations between known Parkinson's risk variants and more severe motor/cognitive symptoms. Also, we replicated previous reports of GBA coding variants (rs2230288: p.E365K; rs75548401: p.T408M) being associated with greater motor and cognitive decline over time, and an APOE E4 tagging variant (rs429358) being associated with greater cognitive deficits in patients. CONCLUSIONS: We identified novel genetic factors associated with heterogeneity of Parkinson's disease. The results can be used for validation or hypothesis tests regarding Parkinson's disease. © 2019 International Parkinson and Movement Disorder Society.
dc.description.sponsorshipThe Intramural Research Program the National Institute on Aging (NIA, Z01-AG000949-02), Biogen Idec, and the Michael J Fox Foundation for Parkinson’s Research.
dc.format.mediumPrint-Electronic
dc.languageeng
dc.publisherWiley
dc.subjectInternational Parkinson's Disease Genomics Consortium
dc.subjectHumans
dc.subjectParkinson Disease
dc.subjectDisease Progression
dc.subjectGlucosylceramidase
dc.subjectOrganic Cation Transport Proteins
dc.subjectAntigens, CD
dc.subjectRisk Assessment
dc.subjectCohort Studies
dc.subjectLongitudinal Studies
dc.subjectCross-Sectional Studies
dc.subjectPhenotype
dc.subjectAdult
dc.subjectAged
dc.subjectAged, 80 and over
dc.subjectMiddle Aged
dc.subjectFemale
dc.subjectMale
dc.subjectGenome-Wide Association Study
dc.subjectBiomarkers
dc.subjectLeucine-Rich Repeat Serine-Threonine Protein Kinase-2
dc.subjectCognitive Dysfunction
dc.titleGenomewide association study of Parkinson's disease clinical biomarkers in 12 longitudinal patients' cohorts.
dc.typeArticle
prism.endingPage1850
prism.issueIdentifier12
prism.publicationDate2019
prism.publicationNameMov Disord
prism.startingPage1839
prism.volume34
dc.identifier.doi10.17863/CAM.42098
dcterms.dateAccepted2019-07-24
rioxxterms.versionofrecord10.1002/mds.27845
rioxxterms.versionAM
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.licenseref.startdate2019-12
dc.contributor.orcidBarker, Roger [0000-0001-8843-7730]
dc.contributor.orcidWilliams-Gray, Caroline [0000-0002-2648-9743]
dc.identifier.eissn1531-8257
rioxxterms.typeJournal Article/Review
pubs.funder-project-idCambridge University Hospitals NHS Foundation Trust (CUH) (146281)
pubs.funder-project-idDepartment of Health (via National Institute for Health Research (NIHR)) (NF-SI-0616-10011)
cam.issuedOnline2019-09-10
cam.orpheus.successThu Jan 30 10:42:48 GMT 2020 - Embargo updated
rioxxterms.freetoread.startdate2020-12-31


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