Abstract Details

Title Genetic Analysis and Natural History of LRRK2 G2019S Parkinson’s Disease

Topic Movement Disorders

Presentation(s) P11 - Poster Session 11 (5:30 PM-6:30 PM)

Poster/Presentation
Number 3-006

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.

Authors/Disclosures
Matthew J. Kmiecik, PhD (23andMe, Inc.) PRESENTER	Dr. Kmiecik has received personal compensation for serving as an employee of 23andMe, Inc.. Dr. Kmiecik has stock in 23andMe, Inc.. The institution of Dr. Kmiecik has received research support from The Michael J. Fox Foundation for Parkinson's Research.
Steven Micheletti (23andMe)	No disclosure on file
Daniella Coker	No disclosure on file
Karl Heilbron	No disclosure on file
Jingchunzi Shi	No disclosure on file
Keaton Stagaman (23andMe)	No disclosure on file
Teresa Sonmez (23andMe)	No disclosure on file
Pierre Fontanillas (23andMe)	No disclosure on file
Suyash Shringarpure	No disclosure on file
Madeleine Schloetter (23andMe)	No disclosure on file
Helen Rowbotham	No disclosure on file
Paul Cannon	No disclosure on file
Janie Shelton (Bristol Myers Squibb)	No disclosure on file
David Hinds (23andMe, Inc.)	No disclosure on file
Joyce Tung	No disclosure on file
Michael Holmes	No disclosure on file
Stella Aslibekyan	No disclosure on file
Lucy Norcliffe-Kaufmann	No disclosure on file

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