Genetic 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 1,286 genotyped LRRK2 G2019S carriers and 109,154 controls, with and without Parkinson’s disease (PD) recruited from the 23andMe Research Cohort. We collected self-reported motor and non-motor symptoms every six 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 modeling and explored the impact of polygenic risk on penetrance. We also computed the genetic ancestry of all LRRK2 G2019S carriers in the 23andMe database and identified regions of the world where carrier frequencies are highest. We observed that despite a one year longer disease duration ( p =0.016), LRRK2 G2019S carriers with PD had similar burden of motor symptoms, yet significantly fewer non-motor symptoms including cognitive difficulties, REM sleep behavior disorder (RBD), and hyposmia (all p-values <0.0002). The cumulative incidence of PD in G2019S carriers by age 60 was 8.66%. G2019S carriers had a 10-fold risk of developing PD versus non-carriers. This rose to a 27-fold risk in G2019S carriers with a PD polygenic risk score in the top 25% versus non-carriers in the bottom 25%. In addition to identifying ancient founding events in people of North African and Ashkenazi descent, our genetic ancestry analyses infer that the G2019S variant was later introduced to Spanish colonial territories in the Americas. Our results suggest LRRK2 G2019S PD appears to be a slowly progressive predominantly motor subtype of PD with a lower prevalence of hyposmia, RBD, and cognitive impairment. This suggests that the current prodromal criteria, which are based on idiopathic PD, may lack sensitivity to detect the early phases of LRRK2 PD in G2019S carriers. We show that polygenic burden may contribute to the development of PD in the LRRK2 G2019S carrier population. Collectively, the results should help support screening programs and candidate enrichment strategies for upcoming trials of LRRK2 inhibitors in early-stage disease. ### Competing Interest Statement At the time of their contributions, authors were employed by and held stock or stock options in 23andMe, Inc. ### Funding Statement We thank The Michael J. Fox Foundation for Parkinson's Research for funding this research (MJK, KS, and LNK). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: All study research participants were >18 years old, US residents, and provided informed consent to volunteer to participate (protocol approval: AAHRPP-accredited Salus IRB). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Model outputs for all logistic regressions are provided as Supplementary Materials. Individual-level data are not publicly available due to participant confidentiality, and in accordance with the IRB-approved protocol under which the study was conducted. No custom code or software was generated as part of the study. Details of all software packages used for data processing and/or analysis may be found in the Methods.