Baig F

Barber T

Barker RA

Ben-Shlomo Y

Burn DJ

Evetts SG

Foltynie T

Grosset DG

Grosset K

Hu MT-M

Klein JC

Lawton M

Malek N

Millin S

Morris HR

Tan MMX

Williams N

Wood N

\ua9 2022 Author(s) (or their employer(s)). Re-use permitted under CC BY. Published by BMJ. Objectives To explore the genetics of four Parkinson\u27s 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\u27s 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 (&lt;5
710e-8) although four variants require further follow-up, meeting a threshold of &lt;1
710e-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

Newcastle University E-Prints

Genetics of validated Parkinson\u27s disease subtypes in the Oxford Discovery and Tracking Parkinson\u27s cohorts

Genetics of validated Parkinson\u27s disease subtypes in the Oxford Discovery and Tracking Parkinson\u27s cohorts

Abstract

Similar works

Full text

Available Versions

Newcastle University E-Prints