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

Lawton, Michael, Tan, Manuela M. X., Ben-Shlomo, Yoav, Baig, Fahd, Barber, Thomas, Klein, Johannes C., Evetts, Samuel G., Millin, Stephanie, Malek, Naveed, Grosset, Katherine, Barker, Roger A., Williams, Nigel ORCID: https://orcid.org/0000-0003-1177-6931, Burn, David J., Foltynie, Thomas, Morris, Huw R., Wood, Nicholas, Grosset, Donald G. and Hu, Michele Tao-Ming 2022. Genetics of validated Parkinson’s disease subtypes in the Oxford Discovery and Tracking Parkinson’s cohorts. Journal of Neurology, Neurosurgery and Psychiatry 93 (9) , pp. 952-959. 10.1136/jnnp-2021-327376

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Abstract

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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Advanced Research Computing @ Cardiff (ARCCA) MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG) Medicine
Additional Information:	License information from Publisher: LICENSE 1: URL: https://creativecommons.org/licenses/by/4.0/, Start Date: 2022-06-21, Type: open-access
Publisher:	BMJ Publishing Group
ISSN:	0022-3050
Date of First Compliant Deposit:	29 June 2022
Date of Acceptance:	25 May 2022
Last Modified:	22 Jul 2024 16:11
URI:	https://orca.cardiff.ac.uk/id/eprint/150876

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