biostudies-literatureUnknown147(6)Kmiecik MJParkinson's ResearchMichael J. Fox Foundation for Parkinson's ResearchMichael J. Fox Foundation for Parkinson's ResearchThe LRRK2 G2019S variant is the most common cause of monogenic Parkinson's disease (PD); however, questions remain regarding the penetrance, clinical phenotype and natural history of carriers. We performed a 3.5-year prospective longitudinal online study in a large number of 1286 genotyped LRRK2 G2019S carriers and 109 154 controls, with and without PD, recruited from the 23andMe Research Cohort. We collected self-reported motor and non-motor symptoms every 6 months, as well as demographics, family histories and environmental risk factors. Incident cases of PD (phenoconverters) were identified at follow-up. We determined lifetime risk of PD using accelerated failure time modelling and explored the impact of polygenic risk on penetrance. We also computed the genetic ancestry of all LRRK2 G2Brain : a journal of neurology1996-2008https://www.ebi.ac.uk/biostudies/studies/S-EPMC11146432biostudies-literatureGenetic analysis and natural history of Parkinson's disease due to the LRRK2 G2019S variant.PMC11146432Shringarpure SBowes JPoznik GDFreyman WTran VSchumacher MWeldon CHBell RKStagaman K23andMe Research TeamKukar KGranka JMLowe MWang WWang XHernandez AWilton PNorcliffe-Kaufmann LShastri AJNguyen DTKwong ACannon PBielenberg JSu QJHolmes MVKmiecik MJO'Connell JLlamas BAAslibekyan SBryc KWetzel MEriksson NFontanillas PRowbotham HMHeilbron KMicheletti SDas SLin KHSelcer LHinds DACoker DShelton JFJiang YAuton ADelloRusso EWong CDMoreno MEPetrakovitz AABabalola EMcIntyre MHNandakumar PReynoso ATat SAJewett EMFilshtein Sonmez TElson SLChaudhary NSTung JYShi JHicks BfalseGenetic analysis and natural history of Parkinson's disease due to the LRRK2 G2019S variant.The LRRK2 G2019S variant is the most common cause of monogenic Parkinson's disease (PD); however, questions remain regarding the penetrance, clinical phenotype and natural history of carriers. We performed a 3.5-year prospective longitudinal online study in a large number of 1286 genotyped LRRK2 G2019S carriers and 109 154 controls, with and without PD, recruited from the 23andMe Research Cohort. We collected self-reported motor and non-motor symptoms every 6 months, as well as demographics, family histories and environmental risk factors. Incident cases of PD (phenoconverters) were identified at follow-up. We determined lifetime risk of PD using accelerated failure time modelling and explored the impact of polygenic risk on penetrance. We also computed the genetic ancestry of all LRRK2 G22024-01-01T00:00:00Z2024 Jun2026-06-03T20:03:51.793Z2026-05-01T03:10:42.934ZS-EPMC111464323880460410.1093/brain/awae073