biostudies-literatureUnknown12(12)Kmiecik MJMichael J. Fox Foundation for Parkinson's ResearchMichael J. Fox Foundation for Parkinson&apos;s Research<h4>Objective</h4>To examine the associations of LRRK2 p.G2019S, GBA1 p.N409S, polygenic risk scores (PRS), and APOE E4 on PD penetrance, risk, and symptoms.<h4>Methods</h4>We conducted a US-based observational case-control study using data from the 23andMe Inc. and Fox Insight Genetic Substudy (FIGS) databases. The total cohort included 7,586,842 participants (n = 35,163 PD); 8791 LRRK2 p.G2019S carriers (565 with PD), 37,427 GBA1 p.N409S carriers (524 with PD), 244 dual LRRK2/GBA1 carriers (37 with PD), and 7.5 million noncarriers (34,037 with PD). PRS was calculated from the most recently published European genome-wide association study. Survival models estimated the cumulative incidence of PD. Logistic regressions estimated the relative odds of reporting motor and non-motor symptoms acAnnals of clinical and translational neurology2482-2494https://www.ebi.ac.uk/biostudies/studies/S-EPMC12698958biostudies-literatureGenetic Modifiers of Parkinson's Disease: A Case-Control Study.PMC12698958Fontanillas PNorcliffe-Kaufmann LRiboldi GMMicheletti SHinds DASchneider RBStagaman K23andMe Research TeamHolmes MVKmiecik MJTat SGuan ATung JYAslibekyan SShi JGottesman JfalseGenetic Modifiers of Parkinson's Disease: A Case-Control Study.<h4>Objective</h4>To examine the associations of LRRK2 p.G2019S, GBA1 p.N409S, polygenic risk scores (PRS), and APOE E4 on PD penetrance, risk, and symptoms.<h4>Methods</h4>We conducted a US-based observational case-control study using data from the 23andMe Inc. and Fox Insight Genetic Substudy (FIGS) databases. The total cohort included 7,586,842 participants (n = 35,163 PD); 8791 LRRK2 p.G2019S carriers (565 with PD), 37,427 GBA1 p.N409S carriers (524 with PD), 244 dual LRRK2/GBA1 carriers (37 with PD), and 7.5 million noncarriers (34,037 with PD). PRS was calculated from the most recently published European genome-wide association study. Survival models estimated the cumulative incidence of PD. Logistic regressions estimated the relative odds of reporting motor and non-motor symptoms ac2025-01-01T00:00:00Z2025 Dec2026-06-06T02:13:34.277Z2026-05-24T03:12:32.537ZS-EPMC126989584092658010.1002/acn3.70176