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Genetics of validated Parkinson's disease subtypes in the Oxford Discovery and Tracking Parkinson's cohorts.

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cam.issuedOnline2022-06-22
dc.contributor.authorLawton, Michael
dc.contributor.authorTan, Manuela Mx
dc.contributor.authorBen-Shlomo, Yoav
dc.contributor.authorBaig, Fahd
dc.contributor.authorBarber, Thomas
dc.contributor.authorKlein, Johannes C
dc.contributor.authorEvetts, Samuel G
dc.contributor.authorMillin, Stephanie
dc.contributor.authorMalek, Naveed
dc.contributor.authorGrosset, Katherine
dc.contributor.authorBarker, Roger A
dc.contributor.authorWilliams, Nigel
dc.contributor.authorBurn, David J
dc.contributor.authorFoltynie, Thomas
dc.contributor.authorMorris, Huw R
dc.contributor.authorWood, Nicholas
dc.contributor.authorGrosset, Donald G
dc.contributor.authorHu, Michele Tao-Ming
dc.contributor.orcidLawton, Michael [0000-0002-3419-0354]
dc.contributor.orcidTan, Manuela Mx [0000-0001-5835-669X]
dc.contributor.orcidKlein, Johannes C [0000-0002-8553-2801]
dc.contributor.orcidFoltynie, Thomas [0000-0003-0752-1813]
dc.contributor.orcidMorris, Huw R [0000-0002-5473-3774]
dc.contributor.orcidHu, Michele Tao-Ming [0000-0001-6382-5841]
dc.date.accessioned2022-06-29T19:49:40Z
dc.date.available2022-06-29T19:49:40Z
dc.date.issued2022-06-22
dc.date.submitted2021-06-14
dc.date.updated2022-06-29T19:49:39Z
dc.description.abstractOBJECTIVES: To explore the genetics of four Parkinson's disease (PD) subtypes that have been previously described in two large cohorts of patients with recently diagnosed PD. These subtypes came from a data-driven cluster analysis of phenotypic variables. METHODS: We looked at the frequency of genetic mutations in glucocerebrosidase (GBA) and leucine-rich repeat kinase 2 against our subtypes. Then we calculated Genetic Risk Scores (GRS) for PD, multiple system atrophy, progressive supranuclear palsy, Lewy body dementia, and Alzheimer's disease. These GRSs were regressed against the probability of belonging to a subtype in the two independent cohorts and we calculated q-values as an adjustment for multiple testing across four subtypes. We also carried out a Genome-Wide Association Study (GWAS) of belonging to a subtype. RESULTS: A severe disease subtype had the highest rates of patients carrying GBA mutations while the mild disease subtype had the lowest rates (p=0.009). Using the GRS, we found a severe disease subtype had a reduced genetic risk of PD (p=0.004 and q=0.015). In our GWAS no individual variants met genome wide significance (<5×10e-8) although four variants require further follow-up, meeting a threshold of <1×10e-6. CONCLUSIONS: We have found that four previously defined PD subtypes have different genetic determinants which will help to inform future studies looking at underlying disease mechanisms and pathogenesis in these different subtypes of disease.
dc.identifier.citationJournal of Neurology, Neurosurgery, and Psychiatry, page jnnp-2021-327376
dc.identifier.doi10.17863/CAM.86005
dc.identifier.eissn1468-330X
dc.identifier.issn0022-3050
dc.identifier.otherjnnp-2021-327376
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/338592
dc.languageen
dc.language.isoeng
dc.publisherBMJ
dc.publisher.urlhttp://dx.doi.org/10.1136/jnnp-2021-327376
dc.subjectGENETICS
dc.subjectPARKINSON'S DISEASE
dc.titleGenetics of validated Parkinson's disease subtypes in the Oxford Discovery and Tracking Parkinson's cohorts.
dc.typeArticle
dcterms.dateAccepted2022-05-25
prism.publicationNameJ Neurol Neurosurg Psychiatry
pubs.funder-project-idParkinson's UK (J-1101, J-1403)
rioxxterms.freetoread.startdate2022-06-21
rioxxterms.licenseref.startdate2022-06-21
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0/
rioxxterms.versionVoR
rioxxterms.versionofrecord10.1136/jnnp-2021-327376

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