Variants in the Niemann–Pick type C gene NPC1 are not associated with Parkinson's disease

Bouchra Ouled Amar Bencheikh; Konstantin Senkevich; Uladzislau Rudakou; Eric Yu; Kheireddin Mufti; Jennifer A. Ruskey; Farnaz Asayesh; Sandra B. Laurent; Dan Spiegelman; Stanley Fahn; Cheryl Waters; Oury Monchi; Yves Dauvilliers; Alberto J. Espay; Nicolas Dupré; Lior Greenbaum; Sharon Hassin-Baer; Guy A. Rouleau; Roy N. Alcalay; Edward A. Fon; Ziv Gan-Or

doi:10.1016/j.neurobiolaging.2020.03.021

Variants in the Niemann–Pick type C gene NPC1 are not associated with Parkinson's disease

Bouchra Ouled Amar Bencheikh, Konstantin Senkevich, Uladzislau Rudakou, Eric Yu, Kheireddin Mufti, Jennifer A. Ruskey, Farnaz Asayesh, Sandra B. Laurent, Dan Spiegelman, Stanley Fahn, Cheryl Waters, Oury Monchi, Yves Dauvilliers, Alberto J. Espay, Nicolas Dupré, Lior Greenbaum, Sharon Hassin-Baer, Guy A. Rouleau, Roy N. Alcalay, Edward A. FonZiv Gan-Or^*

^*Corresponding author for this work

Neurology

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

13 Scopus citations

Abstract

Biallelic variants in NPC1, a gene coding for a lysosomal transmembrane protein involved in cholesterol trafficking, may cause Niemann–Pick disease type C (NPC). A few cases of NPC1 variant carriers with Parkinson's disease (PD) have been reported. In addition, pathologic studies have demonstrated phosphorylated alpha-synuclein and Lewy pathology in brains of NPC patients. Therefore, we aimed to examine whether NPC1 genetic variants may be associated with PD. Full sequencing of NPC1 was performed in 2657 PD patients and 3647 controls from 3 cohorts, using targeted sequencing with molecular inversion probes. A total of 9 common variants and 126 rare variants were identified across the 3 cohorts. To examine their association with PD, regression models adjusted for age, sex, and origin were performed for common variants, and optimal sequence Kernel association test (SKAT-O) was performed for rare variants. After correction for multiple comparisons, common and rare NPC1 variants were not associated with PD. Our results do not support a link between heterozygous variants in NPC1 and PD.

Original language	English
Pages (from-to)	143.e1-143.e4
Journal	Neurobiology of Aging
Volume	93
DOIs	https://doi.org/10.1016/j.neurobiolaging.2020.03.021
State	Published - Sep 2020

Funding

Funders	Funder number
Abbvie, Neuroderm, Neurocrine, Amneal, Adamas, Acadia, Acorda
HBHL
InTrance
Parkinson’s Foundation
USWorldMeds
National Institutes of Health	UL1 TR000040
National Institute of Neurological Disorders and Stroke	K02NS080915
Michael J. Fox Foundation for Parkinson's Research
Brookdale Foundation
McGill University
Sunovion
ACADIA Pharmaceuticals
Consortium canadien en neurodégénérescence associée au vieillissement
Canadian Institutes of Health Research	– 154301
Fonds de Recherche du Québec - Santé
Parkinson Canada
Canada First Research Excellence Fund
H. Lundbeck A/S

Keywords

Lysosomal genes
NPC1
Niemann–Pick disease type C
Parkinson's disease

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Ouled Amar Bencheikh, B., Senkevich, K., Rudakou, U., Yu, E., Mufti, K., Ruskey, J. A., Asayesh, F., Laurent, S. B., Spiegelman, D., Fahn, S., Waters, C., Monchi, O., Dauvilliers, Y., Espay, A. J., Dupré, N., Greenbaum, L., Hassin-Baer, S., Rouleau, G. A., Alcalay, R. N., ... Gan-Or, Z. (2020). Variants in the Niemann–Pick type C gene NPC1 are not associated with Parkinson's disease. Neurobiology of Aging, 93, 143.e1-143.e4. https://doi.org/10.1016/j.neurobiolaging.2020.03.021

@article{f56625e6d5364afa9881ea8f611d97cc,

title = "Variants in the Niemann–Pick type C gene NPC1 are not associated with Parkinson's disease",

abstract = "Biallelic variants in NPC1, a gene coding for a lysosomal transmembrane protein involved in cholesterol trafficking, may cause Niemann–Pick disease type C (NPC). A few cases of NPC1 variant carriers with Parkinson's disease (PD) have been reported. In addition, pathologic studies have demonstrated phosphorylated alpha-synuclein and Lewy pathology in brains of NPC patients. Therefore, we aimed to examine whether NPC1 genetic variants may be associated with PD. Full sequencing of NPC1 was performed in 2657 PD patients and 3647 controls from 3 cohorts, using targeted sequencing with molecular inversion probes. A total of 9 common variants and 126 rare variants were identified across the 3 cohorts. To examine their association with PD, regression models adjusted for age, sex, and origin were performed for common variants, and optimal sequence Kernel association test (SKAT-O) was performed for rare variants. After correction for multiple comparisons, common and rare NPC1 variants were not associated with PD. Our results do not support a link between heterozygous variants in NPC1 and PD.",

keywords = "Lysosomal genes, NPC1, Niemann–Pick disease type C, Parkinson's disease",

author = "{Ouled Amar Bencheikh}, Bouchra and Konstantin Senkevich and Uladzislau Rudakou and Eric Yu and Kheireddin Mufti and Ruskey, {Jennifer A.} and Farnaz Asayesh and Laurent, {Sandra B.} and Dan Spiegelman and Stanley Fahn and Cheryl Waters and Oury Monchi and Yves Dauvilliers and Espay, {Alberto J.} and Nicolas Dupr{\'e} and Lior Greenbaum and Sharon Hassin-Baer and Rouleau, {Guy A.} and Alcalay, {Roy N.} and Fon, {Edward A.} and Ziv Gan-Or",

note = "Publisher Copyright: {\textcopyright} 2020 Elsevier Inc.",

year = "2020",

month = sep,

doi = "10.1016/j.neurobiolaging.2020.03.021",

language = "אנגלית",

volume = "93",

pages = "143.e1--143.e4",

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Ouled Amar Bencheikh, B, Senkevich, K, Rudakou, U, Yu, E, Mufti, K, Ruskey, JA, Asayesh, F, Laurent, SB, Spiegelman, D, Fahn, S, Waters, C, Monchi, O, Dauvilliers, Y, Espay, AJ, Dupré, N, Greenbaum, L , Hassin-Baer, S, Rouleau, GA, Alcalay, RN, Fon, EA & Gan-Or, Z 2020, 'Variants in the Niemann–Pick type C gene NPC1 are not associated with Parkinson's disease', Neurobiology of Aging, vol. 93, pp. 143.e1-143.e4. https://doi.org/10.1016/j.neurobiolaging.2020.03.021

TY - JOUR

T1 - Variants in the Niemann–Pick type C gene NPC1 are not associated with Parkinson's disease

AU - Ouled Amar Bencheikh, Bouchra

AU - Senkevich, Konstantin

AU - Rudakou, Uladzislau

AU - Yu, Eric

AU - Mufti, Kheireddin

AU - Ruskey, Jennifer A.

AU - Asayesh, Farnaz

AU - Laurent, Sandra B.

AU - Spiegelman, Dan

AU - Fahn, Stanley

AU - Waters, Cheryl

AU - Monchi, Oury

AU - Dauvilliers, Yves

AU - Espay, Alberto J.

AU - Dupré, Nicolas

AU - Greenbaum, Lior

AU - Hassin-Baer, Sharon

AU - Rouleau, Guy A.

AU - Alcalay, Roy N.

AU - Fon, Edward A.

AU - Gan-Or, Ziv

PY - 2020/9

Y1 - 2020/9

N2 - Biallelic variants in NPC1, a gene coding for a lysosomal transmembrane protein involved in cholesterol trafficking, may cause Niemann–Pick disease type C (NPC). A few cases of NPC1 variant carriers with Parkinson's disease (PD) have been reported. In addition, pathologic studies have demonstrated phosphorylated alpha-synuclein and Lewy pathology in brains of NPC patients. Therefore, we aimed to examine whether NPC1 genetic variants may be associated with PD. Full sequencing of NPC1 was performed in 2657 PD patients and 3647 controls from 3 cohorts, using targeted sequencing with molecular inversion probes. A total of 9 common variants and 126 rare variants were identified across the 3 cohorts. To examine their association with PD, regression models adjusted for age, sex, and origin were performed for common variants, and optimal sequence Kernel association test (SKAT-O) was performed for rare variants. After correction for multiple comparisons, common and rare NPC1 variants were not associated with PD. Our results do not support a link between heterozygous variants in NPC1 and PD.

AB - Biallelic variants in NPC1, a gene coding for a lysosomal transmembrane protein involved in cholesterol trafficking, may cause Niemann–Pick disease type C (NPC). A few cases of NPC1 variant carriers with Parkinson's disease (PD) have been reported. In addition, pathologic studies have demonstrated phosphorylated alpha-synuclein and Lewy pathology in brains of NPC patients. Therefore, we aimed to examine whether NPC1 genetic variants may be associated with PD. Full sequencing of NPC1 was performed in 2657 PD patients and 3647 controls from 3 cohorts, using targeted sequencing with molecular inversion probes. A total of 9 common variants and 126 rare variants were identified across the 3 cohorts. To examine their association with PD, regression models adjusted for age, sex, and origin were performed for common variants, and optimal sequence Kernel association test (SKAT-O) was performed for rare variants. After correction for multiple comparisons, common and rare NPC1 variants were not associated with PD. Our results do not support a link between heterozygous variants in NPC1 and PD.

KW - Lysosomal genes

KW - NPC1

KW - Niemann–Pick disease type C

KW - Parkinson's disease

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DO - 10.1016/j.neurobiolaging.2020.03.021

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C2 - 32371106

AN - SCOPUS:85084154675

SN - 0197-4580

VL - 93

SP - 143.e1-143.e4

JO - Neurobiology of Aging

JF - Neurobiology of Aging

ER -

Variants in the Niemann–Pick type C gene NPC1 are not associated with Parkinson's disease

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