Polygenic Burden of Parkinson's Disease Risk Stratifies the Prognosis of Isolated Rapid-Eye-movement Disorder: A Preliminary Observational Study

Background: Polygenic burden of Parkinson's disease (PD) risk single nucleotide polymorphisms (SNPs), is associated not only with PD development and age at onset, but also with higher PD penetrance in GBA and LRRK2 carriers. Objectives: To assess the impact of polygenic burden of PD risk SNPs in isolated rapid-eye-movement disorder (iRBD). Methods: In this observational study using the data of the Parkinson's progression marker initiative, we retrospectively reviewed the records of iRBD patients of European-ancestry with genotype data for 90 PD risk SNPs available. We calculated the genetic risk score for PD (PD-GRS) as a weighted sum of those SNPs, and examined the association of PD-PRS with the subsequent course of iRBD patients. Results: 37 IRBD patients (median age = 71.0 years, male = 65.4%) were included. Median follow-up years from the diagnosis was 6.8 years, and 14 patients (38.9%) developed overt alpha-synucleopathies during the follow-up period. PD-GRS was significantly associated with an increased phenoconversion risk [hazard ratio per +1 standard deviation (adjusted for age, sex, and baseline cognitive, motor, autonomic, and olfactory dysfunction as well as principal components 1 to 5 to account for the population stratification) = 7.4 (95% confidence interval, 1.6-34.6)]. Furthermore, iRBD patients with PD-GRS higher than the median showed an accelerated decline in motor function [standardized fixed-effects beta coefficients of the interaction term = 0.08 (95% confidence interval, 0.02-0.14)]. Conclusion: Our study showed the intriguing possibility that the disease course of iRBD patients differed according to the degree of polygenic burden of PD risk SNPs, although future validation is warranted.