Genetic Analysis and Natural History of Parkinson’s Disease Due to the LRRK2 G2019S Variant

Abstract

AbstractTheLRRK2 G2019Svariant 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 genotypedLRRK2 G2019Scarriers 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 allLRRK2 G2019Scarriers 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 G2019Scarriers with PD had similar burden of motor symptoms, yet significantly fewer non-motor symptoms including cognitive difficulties, REM sleep behavior disorder (RBD), and hyposmia (allp-values<0.0002). The cumulative incidence of PD inG2019Scarriers by age 60 was 8.66%.G2019Scarriers had a 10-fold risk of developing PD versus non-carriers. This rose to a 27-fold risk inG2019Scarriers 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 theG2019Svariant was later introduced to Spanish colonial territories in the Americas.Our results suggestLRRK2 G2019SPD 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 ofLRRK2PD inG2019Scarriers. We show that polygenic burden may contribute to the development of PD in theLRRK2 G2019Scarrier population. Collectively, the results should help support screening programs and candidate enrichment strategies for upcoming trials ofLRRK2inhibitors in early-stage disease.