Background and objectives: 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. Methods: LRRK2 and GBA were fully sequenced in 1,309 PD patients and 648 controls from the Columbia and PPMI cohorts, in which GCase activity was measured in dried blood spots by liquid chromatography-tandem mass spectrometry. Results: 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 (OR=1.18, 95%CI=1.09-1.28, p=7.33E-05) in 56,306 PD patients and proxy-cases, and 1.4 million controls. Conclusions: 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.

中文翻译：

---

LRRK2 p.M1646T与葡萄糖脑苷脂酶活性和帕金森氏病有关

背景和目的：LRRK2 p.G2019S帕金森氏病（PD）变体与外周血中葡萄糖脑苷脂酶（GCase）活性升高有关。我们旨在评估其他LRRK2变体与PD的关联及其与GCase活性的关联。方法：对来自哥伦比亚和PPMI队列的1,309名PD患者和648名对照的LRRK2和GBA进行完整测序，其中液相色谱-串联质谱法检测干血斑中的GCase活性。结果：LRRK2 p.M1646T与哥伦比亚大学队列中的GCase活性升高有关（β= 1.58，p = 0.0003），而与PPMI队列中的GCase活性升高相关但不显着（β= 0.29，p = 0.58）。p.M1646T与56,306例PD患者和代理病例以及140万对照者的PD（OR = 1.18，95％CI = 1.09-1.28，p = 7.33E-05）相关。结论：