Objective: To evaluate whether the polygenic risk scores of Parkinson’s disease (PD-PRS) is associated with age at disease onset (AAO), freezing of gait (FOG) or psychosis in a sample of Jewish israeli PD patients.

Background: The PD-PRS summarizes the cumulative effect of multiple genetic variants associated with disease susceptibility. While PD-PRS predicts risk of developing PD, its contribution to clinical heterogeneity among PD patients is unclear.

Method: We performed a retrospective analysis for Jewish PD patients at follow up in the Sheba Movement Disorders Institute, Israel.  PRS were calculated using PRSice-2 based on the most recent PD GWAS summary statistics. Associations between PRS and AAO were assessed with linear regression adjusted for sex. Logistic regression models evaluated associations between PRS and the presence of FOG or psychosis, adjusting for AAO and sex. Time-to-event analyses were performed using Cox proportional hazards models to evaluate associations between PRS and time to FOG or psychosis.  Analyses were repeated excluding LRRK2 and GBA1 variant carriers.

Results: AAO analyses included 560 PD patients (343 males, 61.2%;105 p.Gly2019Ser carriers, 98 GBA1 risk variant carriers and 12 dual gene variant carriers). FOG and psychosis analyses included 369 patients with available phenotype data, mean AAO for 59.2±11.4 years, and mean disease duration at last evaluation was 14.2±7.6 years. The PD-PRS was not significantly associated with AAO (β = −0.32 years per SD increase in PRS, 95% CI −1.30 to 0.67, p = 0.53). Similarly, PD-PRS was not associated with the presence of FOG (OR = 0.95, 95% CI 0.75–1.19, p = 0.64) or psychosis (OR = 0.95, 95% CI 0.73–1.23, p = 0.71). Cox regression analyses showed no association between PRS and time to FOG (HR = 0.99, 95% CI 0.85–1.15, p = 0.87) or time to psychosis (HR = 1.00, 95% CI 0.80–1.23, p = 0.97). Results were similar when analyses were restricted to non-carriers of variants, across all models.

Conclusion: In this cohort of Jewish people with PD, the PD-PRS was not associated with AAO, occurrence, or timing of FOG or psychosis. These null findings may reflect limited sample size and insufficient statistical power. Larger, well-powered studies are needed to clarify the contribution of PD genetic architecture to clinical heterogeneity

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MDS Abstracts - https://www.mdsabstracts.org/abstract/lack-of-association-between-polygenic-risk-scores-for-parkinsons-disease-and-age-at-onset-freezing-of-gait-or-psychosis/