LRRK2 p.M1646T is associated with glucocerebrosidase activity and with Parkinson's disease

The LRRK2 p.G2019S Parkinson's disease (PD) variant is associated with elevated glucocerebrosidase (GCase) activity in peripheral blood. We aimed to evaluate the association of other LRRK2 variants with PD and its association with GCase activity. LRRK2 and GBA were fully sequenced in 1123 PD patients and 576 controls from the Columbia and PPMI cohorts, in which GCase activity was measured in dried blood spots by liquid chromatography-tandem mass spectrometry. LRRK2 p.M1646T was associated with increased GCase activity in the Columbia University cohort (β = 1.58, p = 0.0003), and increased but not significantly in the PPMI cohort (β = 0.29, p = 0.58). p.M1646T was associated with PD (odds ratio = 1.18, 95% confidence interval = 1.09–1.28, p = 7.33E-05) in 56,306 PD patients and proxy-cases, and 1.4 million controls. Our results suggest that the p.M1646T variant is associated with risk of PD with a small effect and with increased GCase activity in peripheral blood.