Penetrance of Parkinson's disease in GBA1 carriers is depending on the variant severity and polygenic background

Background: Heterozygous variants in the GBA1 gene cause Parkinson's disease (PD) with variable penetrance and have been classified into severe, mild, and PD-specific risk variants based on their association with Gaucher's disease (GD; mild and severe) or PD (risk variants). Polygenic risk scores (PRS) further modify PD susceptibility and may influence the age of onset in GBA1 variant carriers. Our study investigates the interaction between a genome wide PRS and pathogenic GBA1 variants (GBA1PVs), focusing on how established combined PD risk polymorphisms may influence GBA1-related PD risk across different levels of GBA1-mediated pathogenicity. Methods: GBA1 variants were identified from whole exome sequencing data in the UK Biobank (UKB) cohort and from GBA1-targeted PacBio sequencing in the Luxembourg Parkinson's Study (LuxPark). PRSs were calculated for all participants using established genome-wide significant SNPs, excluding variants within the GBA1 locus, and then categorized based on both PRS levels and GBA1PVs carrier status. Carriers of GBA1PVs were further divided into "severe (Gaucher-related) +mild (PD-related)" and "risk" groups. To evaluate the relationship between PRS, GBA1PVs carrier status or severity, and PD risk, logistic regression and Cox proportional hazards regression were conducted with disease presence as the dependent variable. Results: We identified GBA1PVs in 8.8% of PD patients in the UKB discovery cohort and 9.9% in the LuxPark replication cohort. GBA1PVs carriers had consistently higher PD risk compared to non-carriers across all PRS categories. In UKB, GBA1PVs carriers in the highest PRS category had a 2.3-fold increased risk of PD (OR: 2.34; 95% CI, 2.08-2.63) and cumulative incidence of 67% by the age of 75, while those in LuxPark had a 1.6-fold higher risk (OR: 1.64; 95% CI, 1.52-1.76), and cumulative incidence of 81% at the age of 75. Carriers of "severe+mild" GBA1 variants had nearly double the risk of PD compared to "risk" variant carriers, with ORs ranging from 2.05 to 3.69 in UKB and 1.73 to 1.98 in LuxPark. The interaction between the PRSs and GBA1PVs severity was similar in the two cohorts. Conclusions: Our findings demonstrate that GBA1PVs carrier status and severity significantly impact PD risk, with severe variants conferring higher risk than risk ones. Additionally, PRS consistently increases both PD risk and GBA1PVs penetrance in an additive manner across all variant types, defining a genetic background that influences PD penetrance in GBA1PVs carriers. The presence of additional PD-associated risk variants in GBA1 carriers defines new avenues to incorporate PRS and genetic risk data into future clinical trial design and genetic counselling in GBA1-associated PD.