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

Yuri L Sosero; Eric Yu; Lynne Krohn; Uladzislau Rudakou; Kheireddin Mufti; Jennifer A Ruskey; Farnaz Asayesh; Sandra B Laurent; Dan Spiegelman; Stanley Fahn; Cheryl Waters; S Pablo Sardi; Sara Bandres-Ciga; Roy N Alcalay; Ziv Gan-Or; Konstantin Senkevich

doi:10.1016/j.neurobiolaging.2021.02.018

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

Neurobiol Aging. 2021 Jul:103:142.e1-142.e5. doi: 10.1016/j.neurobiolaging.2021.02.018. Epub 2021 Feb 28.

Authors

Affiliations

¹ Montreal Neurological Institute, McGill University, Montréal, QC, Canada; Department of Human Genetics, McGill University, Montréal, QC, Canada.
² Montreal Neurological Institute, McGill University, Montréal, QC, Canada; Department of Neurology and neurosurgery, McGill University, Montréal, QC, Canada.
³ Department of Neurology and neurosurgery, McGill University, Montréal, QC, Canada.
⁴ Montreal Neurological Institute, McGill University, Montréal, QC, Canada.
⁵ Department of Neurology, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY, USA.
⁶ Rare and Neurological Diseases Therapeutic Area, Sanofi, Framingham, MA, USA.
⁷ Molecular Genetics Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
⁸ Department of Neurology, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY, USA; Taub Institute for Research on Alzheimer's Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY, USA.
⁹ Montreal Neurological Institute, McGill University, Montréal, QC, Canada; Department of Human Genetics, McGill University, Montréal, QC, Canada; Department of Neurology and neurosurgery, McGill University, Montréal, QC, Canada.
¹⁰ Montreal Neurological Institute, McGill University, Montréal, QC, Canada; Department of Neurology and neurosurgery, McGill University, Montréal, QC, Canada. Electronic address: konstantin.senkevich@mcgill.ca.

PMID: 33781610
PMCID: PMC8178224
DOI: 10.1016/j.neurobiolaging.2021.02.018

Abstract

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.

Keywords: GBA; Glucocerebrosidase; LRRK2; Parkinson's disease.

Publication types

Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't

MeSH terms

Aged
Cohort Studies
Female
Genetic Association Studies*
Genetic Variation / genetics*
Glucosylceramidase / blood*
Humans
Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / genetics*
Male
Middle Aged
Parkinson Disease / enzymology*
Parkinson Disease / genetics*
Risk

Substances

LRRK2 protein, human
Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
Glucosylceramidase

Abstract

Publication types

MeSH terms

Substances

Grants and funding