Objective:

To conduct a prospective longitudinal observational study of LRRK2 G0219S carriers and non-carriers with and without Parkinson disease (PD).

Background:

Despite LRRK2 G2019S variant carriers having a high risk of PD, little is known about their natural history.

Design/Methods:

Ancestry analysis was performed on all G2019S carriers at 23andMe (n=12,855). In addition, 1,286 genetically-confirmed G2019S carriers and 109,155 randomly selected non-carriers were enrolled in a 3.5-year prospective online study. Surveys were administered every 6-months to document the emergence of motor/non-motor features. Baseline neurological symptoms in manifest PD cases with (n=188) and without (n=2,113) the G2019S variant were compared. We modeled disease penetrance using accelerated failure time analysis. Polygenic risk scores (PRS) were constructed from previously-published data, removing the LRRK2 locus.

Results:

In addition to ancient founding events in North African and Ashkenazi Jewish populations, ancestry analysis showed the G2019S variant was later introduced to the Spanish colonial territories. Carrying the G2019S variant results in a 10-fold risk of developing PD. This risk increases to 27-fold in G2019S carriers with a PD PRS in the top 25% versus non-carriers in the bottom 25%. Relative to idiopathic PD, the G2019S variant results in a similar burden of motor symptoms, but fewer cognitive difficulties, lower rates of REM behavior disorder, and less hyposmia (p-values<0.001).

Conclusions:

G2019S carriers have a mostly motor-subtype of PD with fewer non-motor symptoms; suggesting that the current prodromal criteria may underestimate their risk of PD. Importantly, a higher polygenicity burden increases the risk of PD in G2019S carriers, suggesting PRS may be useful for selecting candidates at risk of phenoconversion for prodromal trials. The ancestry results should help inform screening programs to detect cases of LRRK2 PD in areas with a high density of G2019S carriers.