Objective: To evaluate if updated polygenic risk scores (PRS) for Parkinson’s disease (PD) are associated with the development of incident PD amongst a cohort of healthy older adults.

Background: Increasingly well-powered genome-wide association studies (GWAS) continue to reveal genetic risk variants for PD. To date, over 150 risk variants have been identified. PD-specific PRS thus require constant iteration in light of these new findings. Here, we test the predictive value of an updated PD-PRS, based on the latest 2025 PD meta-GWAS, in the large PREDICT-PD cohort.

Method: The study population was drawn from the PREDICT-PD study, which recruits healthy adults aged 50-80 in the United Kingdom, without neurodegenerative disease at baseline. Participants are followed up longitudinally both actively and passively (NHS data linkage) to determine the development of PD. Some participants are genotyped through collaboration with the Global Parkinson’s Genetics Program (GP2). PD-PRS could be computed for 2,006 individuals, of whom 17 developed incident PD. PD-PRS was derived from European-ancestry GWAS summary statistics. PRS was computed with a linkage disequilibrium clumping and thresholding approach, and standardised to z-scores. Associations between PD-PRS and development of incident PD were tested using Cox regression models, adjusted for age and sex. Additional analyses explored whether PD-PRS improved risk estimation of PD when combined with prodromal risk algorithm scores (PREDICT-PD and Movement Disorders Society (MDS) scores).

Results: PD-PRS was associated with increased risk of developing PD (HR 1.28, 0.79-2.07), though this was not statistically significant, likely due to the sample size and the limited number of incident cases. Adding PD-PRS as an explanatory variable to Cox regression models studying the association between PREDICT-PD and MDS algorithm scores and incident PD did not improve the estimation of new PD diagnoses.

Conclusion: The observed direction of effect suggests PD-PRS may have a role in PD prediction efforts. We suggest our work is currently underpowered to demonstrate statistical significance. However, as the number of individuals genotyped through GP2 increases, we will examine PD-PRS in better-powered cohorts in subsequent analyses.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/disease-specific-polygenic-risk-scores-and-development-of-incident-parkinsons-disease-in-a-large-cohort-of-healthy-older-adults/