Objective: To replicate findings from previous studies reporting an association between the α-synuclein (SNCA) rs356219 genetic variant and progression to key outcomes in Parkinson’s disease (PD), in a large sample of patients representative of the general PD population, followed up to 10 years from diagnosis.

Background: There is growing interest in genetic variants as biomarkers of disease progression in PD. Recently, an association between SNCA rs356219 and motor fluctuations was reported in a population-based cohort of incident PD. Further, faster progression to Hoehn and Yahr stage 3 (HY3) was reported for this variant specifically in carriers of glucocerebrosidase (GBA) mutations in the same sample of patients. No associations with time to dementia (PDD), death, or dyskinesias were reported. These findings warrant replication in an independent PD population.

Method: 843 PD patients from five population-based, prospective cohorts of incident PD (ICICLE-PD, NYPUM, ParkWest, PICNICS, and PINE) from Parkinson’s Incidence Cohorts Collaboration (PICC) were genotyped for SNCA rs356219 and screened for GBA mutations. We used Cox regression to evaluate the impact of rs356219 on progression to five outcomes in the first 10 years from PD diagnosis: motor fluctuations, dyskinesias, HY3, PDD, and death, after excluding those with the outcome at diagnosis. We also investigated the impact of rs356219 in GBA mutation carriers.

Results: Of the 843 PD patients, information was available for all for PDD and death, 684 for motor fluctuations, 694 for dyskinesias, and 698 for HY3. Patients were followed for a median of 7.1 years. The cumulative proportion of the study outcomes at 10 years from diagnosis was 81.4% for motor fluctuations, 63.2% for dyskinesias, 71.5% for HY3, 48.7% for PDD, and 67.7% for death. The rs356219 variant had no significant effect on progression to any of the study outcomes, neither as individual genetic variant nor in the subgroup of 84 patients with GBA-PD.

Conclusion: We found no evidence for worse disease outcomes in carriers of the PD-risk variant rs356219, suggesting that this variant might not have a strong impact on disease progression. This is in line with previous evidence on separate genetic landscapes driving PD risk and progression. To detect the effect of this variant, studies with longer follow-up and larger cohorts of patients carrying GBA mutations might be warranted.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/no-evidence-for-the-impact-of-snca-rs356219-on-parkinsons-disease-progression/