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Lookup NU author(s): Professor David Burn
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2022 Author(s) (or their employer(s)). Re-use permitted under CC BY. Published by BMJ. Objectives 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.
Author(s): Lawton M, Tan MMX, Ben-Shlomo Y, Baig F, Barber T, Klein JC, Evetts SG, Millin S, Malek N, Grosset K, Barker RA, Williams N, Burn DJ, Foltynie T, Morris HR, Wood N, Grosset DG, Hu MT-M
Publication type: Article
Publication status: Published
Journal: Journal of Neurology, Neurosurgery and Psychiatry
Year: 2022
Volume: 93
Issue: 9
Pages: 952-959
Print publication date: 01/09/2022
Online publication date: 22/06/2022
Acceptance date: 25/05/2022
Date deposited: 13/10/2022
ISSN (print): 0022-3050
ISSN (electronic): 1468-330X
Publisher: BMJ Publishing Group
URL: https://doi.org/10.1136/jnnp-2021-327376
DOI: 10.1136/jnnp-2021-327376
PubMed id: 35732412
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