SUMMARYParkinson’s Disease (PD) is the second most common and fastest-growing neurological disorder. Polygenic Risk Scores (PRS) using hundreds to thousands of PD-associated variants support polygenic heritability. Here, for the first time, we apply a genome-wide polygenic risk score approach using 6.2 million variants to compute a PD genome-wide polygenic risk score (PD-GPRS) via the LDPred algorithm. PD-GPRS validation and testing used Accelerating Medicines Partnership – Parkinson’s Disease (AMP-PD) and FinnGen Consortia genomic data from 1,654 PD Cases and 79,123 Controls. PD odds for the top 8%, 2.5%, and 1% of PD-GPRS were three-, four-, and seven times greater compared with lower percentiles, respectively (p<1e-10). PD age of onset and MDS-UPDRS motor scores also differed by PD-GPRS decile. Enrichment for phagosome related, dopamine signaling, immune related, and neuronal signaling pathways was found for genes nearest high PD-GPRS variants identified by MAF analysis. PD-GPRS offers a promising screening tool to identify high-risk individuals for preventive lifestyle or new drug therapy trials.In BriefIn Han and Teeple et al., Parkinson’s Disease inherited risk is quantified by a genome-wide polygenic risk score (PD-GPRS) approach using 6.2 million variants and data from 80,777 individuals. For the top 2.5% and 1% of PD-GPRS, individuals had five- and seven-fold greater odds of PD, respectively. PD-GPRS was found to be associated with overall PD risk, earlier age of onset, and MDS-UPDRS motor scores. Genes nearest to variants observed at higher frequencies among high-GPRS individuals are enriched for PD-implicated pathways.HIGHLIGHTS-Parkinson’s Disease genome-wide polygenic risk score (PD-GPRS) calculated from 6.2 million variants identifies individuals with inherited clinically significant increased neurodegeneration risk.-Top percentile PD-GPRS individuals were found to have up to seven-fold greater odds of PD and earlier age at PD diagnosis.-PD-GPRS scores correlated with all-subjects cohort mean MDS-UPDRS motor scores.-Pathway analysis of genes adjacent to frequently occurring variants in the high PD-GPRS population identified polygenic risk contributions for variations in PD-implicated pathways including dopamine signaling, immune responses, and autophagy pathways.
Penetrance of Parkinson's Disease in
LRRK2
p.G2019S Carriers Is Modified by a Polygenic Risk Score
