Genetic analysis and natural history of Parkinson's disease due to the LRRK2 G2019S variant

Abstract

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 G2019S carriers in the 23andMe database and identified regions of the world where carrier frequencies are highest. We observed that despite a 1 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 behaviour disorder (RBD) and hyposmia (all P-values ≤ 0.0002). The cumulative incidence of PD in G2019S carriers by age 80 was 49%. 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 programmes and candidate enrichment strategies for upcoming trials of LRRK2 inhibitors in early-stage disease.

Keywords: LRRK2 G2019S; Parkinson’s disease; REM sleep behaviour disorder; movement disorders; natural history; polygenic risk score.

Figure 1

Parkinson’s impact project study design and analysis plan. Flow chart that shows recruitment of consented participants, classification according to LRRK2 G2019S carrier status and Parkinson’s disease (PD) diagnosis. The older non-manifest subgroup was selected based on age at risk of PD (≥42.41 years, i.e. within 2 SD of age of PD diagnosis for LRRK2 G2019S carriers). LRRK2 G2019S carriers received a similar survey every 6 months. Non-carriers were asked to report any new diagnosis of PD every 12 months. Pink = LRRK2 G2019S carriers; blue = non-carriers.

Figure 2

Ancestry of LRRK2 G2019S carriers. Ancestry and geographic origins of individuals who carry the LRRK2 G2019S mutation. (A) Frequency of LRRK2 G2019S carriers based on participant-reported grandparent birth countries. Green clouds correspond to subnational locations with the highest frequency of carriers based on kernel density estimates. (B) The genetic structure of the seven groups identified in LRRK2 G2019S carriers. Groups are arranged in a graph using ForceAtlas2 orientation based on the mean pairwise identical by descent (IBD) sharing rate. (C) Ancestry composition of carriers belonging to each genetic group. The mean genome-wide ancestry of individuals is displayed above, with the ancestry at LRRK2 reflected below.

Figure 3

Relative to non-carrier PD, LRRK2 G2019S PD reported lower symptomatic burden in cognitive, memory, autonomic, RBD and olfactory domains. Symptoms were clustered by domain. Bars show the percentage of LRRK2 G2019S Parkinson’s disease (PD) carriers and non-carrier PD that self-reported a symptom. Differences between groups were estimated using odds ratios (OR) from logistic regressions adjusted for age, sex, education and disease duration. Horizontal black lines show prevalence reported by age- and sex-matched non-carrier controls (not included in modelling). Schematic of the brain shows corresponding neuropathological sites underlying symptom burden for LRRK2 G2019S PD. Aggregated symptom burden was calculated by averaging the percentage of reported symptoms across each phenotype domain in LRRK2 G2019S PD. Note the similarities in the reported frequency of motor symptoms, but lower prevalence for symptoms corresponding to regions outside the basal ganglia (e.g. RBD, smell, cognition). *P < 0.05; **P < 0.01; ***P < 0.001. ED = erectile dysfunction; MCI = mild cognitive impairment diagnosis; OH = orthostatic hypotension; OR = odds ratio comparing LRRK2 G2019S PD and non-carrier PD; RBD = REM sleep behaviour disorder. The brain illustration and colour shading was reprinted with modifications from Braak et al. with permission from Elsevier.

Figure 4

Survival curves with Kaplan-Meier estimation show a steeper decline in PD-free survival in LRRK2 G2019S carriers (n = 1154) relative to non-carriers (n = 97 308). Curves were smoothed using generalized additive models to protect data privacy. Shading depicts 95% confidence intervals. PD = Parkinson’s disease.

Figure 5

Associations between PRS and PD prevalence for participants ≥ 40 years of age. (A) Distributions of the modified polygenic risk scores (PRS) adjusted for age, sex and ancestry principal components (PCs). Diamonds indicate median PRS. Non-manifest non-carriers were the non-carrier controls. (B) Odds ratios of Parkinson’s disease (PD) diagnosis between LRRK2 G2019S carriers and non-carriers stratified by PRS percentile groups: low (0%–25%), intermediate (25%–75%), high (75%–100%). Logistic regressions were adjusted for age, sex and ancestry PCs, and non-carriers with intermediate PRS were the reference group. Error bars are 95% confidence intervals (CIs). (C) Predicted PD odds ratios between LRRK2 G2019S carriers and non-carriers referenced to non-carriers with median PRS across PRS deciles. Shading denotes 95% CIs. Interm. = intermediate; SD = standard deviation.