Genetic Analysis and Natural History of LRRK2 G2019S Parkinson’s Disease (P11-3.006)

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

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

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.

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).

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.

Disclosure: 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. Dr. Micheletti has received personal compensation for serving as an employee of 23andMe. Dr. Micheletti has stock in 23andMe. The institution of Dr. Micheletti has received research support from 23andMe. Miss Coker has received personal compensation for serving as an employee of 23andMe, Inc. Dr. Heilbron has received personal compensation for serving as an employee of 23andMe. Dr. Heilbron has stock in 23andMe. Dr. Heilbron has received research support from Alexander von Humboldt Stiftung. Ms. Shi has received personal compensation for serving as an employee of 23andMe, Inc. Ms. Shi has stock in 23andMe, Inc. Dr. Stagaman has received personal compensation for serving as an employee of 23andMe. The institution of Dr. Stagaman has received research support from Michael J Fox Foundation. Dr. Sonmez has received personal compensation for serving as an employee of 23andMe. Dr. Sonmez has stock in 23andMe. Dr. Fontanillas has received personal compensation for serving as an employee of 23andMe. Dr. Fontanillas has stock in 23andMe. Dr. Shringarpure has received personal compensation for serving as an employee of 23andMe. Dr. Shringarpure has stock in 23andMe. Mrs. Schloetter has received personal compensation for serving as an employee of 23andMe. Mrs. Schloetter has stock in 23andMe. Helen Rowbotham has received personal compensation for serving as an employee of 23andMe. Helen Rowbotham has stock in 23andMe. Mr. Cannon has received personal compensation for serving as an employee of 23andMe. An immediate family member of Mr. Cannon has received personal compensation in the range of $50,000-$99,999 for serving as a Consultant for many companies. An immediate family member of Mr. Cannon has received personal compensation in the range of $0-$499 for serving as an officer or member of the Board of Directors for GeneproDX. An immediate family member of Mr. Cannon has received personal compensation in the range of $10,000-$49,999 for serving as an officer or member of the Board of Directors for GMDX. Mr. Cannon has stock in many companies. An immediate family member of Mr. Cannon has stock in many companies. Mr. Cannon has received personal compensation in the range of $100,000-$499,999 for serving as a employee with 23andMe. An immediate family member of Mr. Cannon has received personal compensation in the range of $500,000-$999,999 for serving as a consultant (single member LLC) with many companies. Dr. Shelton has received personal compensation for serving as an employee of 23andMe. Dr. Shelton has received personal compensation for serving as an employee of Bristol Myers Squibb. Mr. Hinds has received personal compensation for serving as an employee of 23andMe, Inc. Mr. Hinds has stock in 23andMe, Inc. Dr. Tung has received personal compensation for serving as an employee of 23andMe, Inc. Dr. Tung has stock in 23andMe, Inc. Dr. Holmes has received personal compensation for serving as an employee of 23andMe. Dr. Holmes has stock in BridgeBio. Dr. Holmes has stock in CYTOKINETICS. Dr. Holmes has stock in ELI LILLY. Dr. Holmes has stock in NOVO NORDISK. Dr. Holmes has stock in PFIZER. Dr. Holmes has stock in 23andMe. The institution of Dr. Holmes has received research support from British Heart Foundation. Dr. Aslibekyan has received personal compensation for serving as an employee of 23andMe, Inc. Dr. Aslibekyan has stock in 23andMe, Inc. Dr. Norcliffe-Kaufmann has received personal compensation for serving as an employee of 23andMe, Inc. Dr. Norcliffe-Kaufmann has stock in 23andMe.