Objective: This study’s primary objective is to use Hoehn & Yahr (HY) staging to determine the genetic influence on motor progression through a longitudinal analysis of time taken to reach HY stage 3 or more (HY3). A secondary aim is to compare the genetic architecture of PD risk with disease progression.

Background: Parkinson’s disease (PD) progression is heterogeneous and contributing genetic factors are not well understood. The HY staging scale is a common measure of motor progression¹. Previous time-to-event genome-wide association studies (GWAS) of reaching HY3 have reported some genome-wide significant loci but very little replication across studies demonstrates the need for larger, well-powered studies^2,3. Leveraging GP2 cohort data increases statistical power to confidently characterize genetic factors linked to faster motor progression in PD.

Method: Clinical data, including baseline age, sex, disease duration, and medication, was collected from 12,065 individuals across 39 GP2 participating cohorts. DNA samples were genotyped with NeuroBoosterArray and imputed against TopMed r3. The primary analysis was a time-to-first occurrence of HY3 GWAS from baseline assessment using a Cox proportional hazard model (CPH) adjusting for age, sex, disease duration, and 10 genetic principal components. To maximize statistical power, results were meta-analyzed with results generated from 5 non-GP2 datasets including a further 3,872 participants.

Results: The GP2 data included 12,065 individuals (35.7% female, 68.8% European ancestry) with data available for baseline age (65.7 ± 10.3 years), disease duration (5.7 ± 6.5 years), and HY stage (1.9 ± 1.1). The discovery GP2 CPH analysis included 5,100 participants who had follow-up visits with a median follow-up of 8.0 [6.0, 12.0] years. The median time to HY3 across the study was 8.83 years. The combined CPH meta-analysis, including external cohorts, comprised 8,972 individuals with a median follow-up of 11.6 [6.0, 17.4] years. Preliminary results did not reach genome-wide significance, but stratified analyses nominated some variants associated with progression.

Conclusion: Preliminary results indicate distinct genetic architectures for disease risk and disease progression in PD, emphasizing progression heterogeneity. Larger longitudinal studies are needed to detect robust signals and provide novel perspectives on disease pathophysiology and therapeutic interventions.

References: 1. Schrag, A., Spottke, A., Quinn, N. P. & Dodel, R. Comparative responsiveness of Parkinson’s disease scales to change over time. Mov. Disord. 24, 813–818 (2009).
2. Tan, M. M. X. et al. Genome-wide determinants of mortality and motor progression in Parkinson’s disease. NPJ Parkinsons Dis. 10, 113 (2024).
3. Iwaki, H. et al. Genetic risk of Parkinson disease and progression:: An analysis of 13 longitudinal cohorts. Neurol. Genet. 5, e348 (2019).

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MDS Abstracts - https://www.mdsabstracts.org/abstract/exploring-genetic-contributions-to-disease-progression-on-hoehn-and-yahr-scales-in-parkinsons-disease/