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

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^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

16 Scopus citations

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.

Original language	English
Pages (from-to)	142.e1-142.e5
Journal	Neurobiology of Aging
Volume	103
DOIs	https://doi.org/10.1016/j.neurobiolaging.2021.02.018
State	Published - Jul 2021
Externally published	Yes

Funding

Funders	Funder number
Amneal
HBHL
International Parkinson Disease Genomics Consortium
Kashiv Pharma
Lysosomal Therapeutics Inc.
Parkinson's Progression Markers Initiative
Sun Pharma Advanced Research Co. LTD
US World Meds
National Institutes of Health	UL1 TR000040
National Institute on Aging
National Institute of Neurological Disorders and Stroke	K02NS080915
Michael J. Fox Foundation for Parkinson's Research
Brookdale Foundation
Roche
Biogen
McGill University
Acadia University
Parkinson's Foundation
Juno Therapeutics
Consortium canadien en neurodégénérescence associée au vieillissement
Fonds de Recherche du Québec - Santé
Parkinson Canada
Canada First Research Excellence Fund

Keywords

GBA
Glucocerebrosidase
LRRK2
Parkinson's disease

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10.1016/j.neurobiolaging.2021.02.018

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Sosero, Y. L., Yu, E., Krohn, L., Rudakou, U., Mufti, K., Ruskey, J. A., Asayesh, F., Laurent, S. B., Spiegelman, D., Fahn, S., Waters, C., Sardi, S. P., Bandres-Ciga, S., Alcalay, R. N., Gan-Or, Z., & Senkevich, K. (2021). LRRK2 p.M1646T is associated with glucocerebrosidase activity and with Parkinson's disease. Neurobiology of Aging, 103, 142.e1-142.e5. https://doi.org/10.1016/j.neurobiolaging.2021.02.018

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title = "LRRK2 p.M1646T is associated with glucocerebrosidase activity and with Parkinson's disease",

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",

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

note = "Publisher Copyright: {\textcopyright} 2021 Elsevier Inc.",

year = "2021",

month = jul,

doi = "10.1016/j.neurobiolaging.2021.02.018",

language = "אנגלית",

volume = "103",

pages = "142.e1--142.e5",

journal = "Neurobiology of Aging",

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Sosero, YL, Yu, E, Krohn, L, Rudakou, U, Mufti, K, Ruskey, JA, Asayesh, F, Laurent, SB, Spiegelman, D, Fahn, S, Waters, C, Sardi, SP, Bandres-Ciga, S, Alcalay, RN, Gan-Or, Z & Senkevich, K 2021, 'LRRK2 p.M1646T is associated with glucocerebrosidase activity and with Parkinson's disease', Neurobiology of Aging, vol. 103, pp. 142.e1-142.e5. https://doi.org/10.1016/j.neurobiolaging.2021.02.018

TY - JOUR

T1 - LRRK2 p.M1646T is associated with glucocerebrosidase activity and with Parkinson's disease

AU - Sosero, Yuri L.

AU - Yu, Eric

AU - Krohn, Lynne

AU - Rudakou, Uladzislau

AU - Mufti, Kheireddin

AU - Ruskey, Jennifer A.

AU - Asayesh, Farnaz

AU - Laurent, Sandra B.

AU - Spiegelman, Dan

AU - Fahn, Stanley

AU - Waters, Cheryl

AU - Sardi, S. Pablo

AU - Bandres-Ciga, Sara

AU - Alcalay, Roy N.

AU - Gan-Or, Ziv

AU - Senkevich, Konstantin

PY - 2021/7

Y1 - 2021/7

N2 - 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.

AB - 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.

KW - GBA

KW - Glucocerebrosidase

KW - LRRK2

KW - Parkinson's disease

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U2 - 10.1016/j.neurobiolaging.2021.02.018

DO - 10.1016/j.neurobiolaging.2021.02.018

M3 - ???researchoutput.researchoutputtypes.contributiontojournal.article???

C2 - 33781610

AN - SCOPUS:85103261435

SN - 0197-4580

VL - 103

SP - 142.e1-142.e5

JO - Neurobiology of Aging

JF - Neurobiology of Aging

ER -

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

Abstract

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