An improved polygenic score for Parkinson’s disease partly explains variable penetrance of genetic Parkinson’s disease

While genetic causes are identified in up to 15% of all Parkinson’s disease (PD) patients, the remaining idiopathic PD (iPD) patients are attributed to polygenic risk, environmental and lifestyle factors, and interactions thereof. We applied five advanced polygenic score (PGS) tools to data from 1,762 iPD patients and 4,227 healthy controls of European ancestry, resulting in the development of a novel iPD-PGS with significantly improved discriminative performance compared to existing models with an AUC of 0.680 (95% confidence interval (-CI): [0.665, 0.695]). Validation in independent cohorts confirmed its robustness. Notably, patients with early-onset iPD exhibited markedly high PGS values when compared to late-onset iPD patients and healthy controls, underlining the high polygenetic burden in these individuals. We subsequently applied our novel iPD-PGS to carriers of heterozygous PRKN variants and GBA1 coding risk variants. In both cases, our findings suggest that part of the penetrance in these genetic forms of PD can be explained by the same polygenic alterations as observed mitigating iPD. The discriminative potential was greater for GBA1 than for PRKN ( GBA1 : AUC=0.639, 95%-CI=[0.590, 0.687], PRKN : AUC=0.594, 95%-CI=[0.501, 0.687]). Our study highlights the potential of advanced PGSs in PD research, particularly for understanding varying penetrance in genetic PD and identifying high-risk individuals.