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

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 demonstra...

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Bibliographic Details
Published in:Neurobiology of aging 2020-09, Vol.93, p.143.e1-143.e4
Main Authors: Ouled Amar Bencheikh, Bouchra, Senkevich, Konstantin, Rudakou, Uladzislau, Yu, Eric, Mufti, Kheireddin, Ruskey, Jennifer A., Asayesh, Farnaz, Laurent, Sandra B., Spiegelman, Dan, Fahn, Stanley, Waters, Cheryl, Monchi, Oury, Dauvilliers, Yves, Espay, Alberto J., Dupré, Nicolas, Greenbaum, Lior, Hassin-Baer, Sharon, Rouleau, Guy A., Alcalay, Roy N., Fon, Edward A., Gan-Or, Ziv
Format: Article
Language:English
Subjects:
Aged
Alpha-Synuclein
Female
Genetic Association Studies
Genetic Variation
Genetics
Human genetics
Humans
Intracellular Signaling Peptides and Proteins
Intracellular Signaling Peptides and Proteins - genetics
Life Sciences
Lysosomal genes
Lysosomes
Lysosomes - genetics
Male
Middle Aged
Negative Results
Neurobiology
Neurons and Cognition
Niemann-Pick C1 Protein
Niemann-Pick Disease, Type C
Niemann-Pick Disease, Type C - genetics
Niemann-Pick Disease, Type C - metabolism
NPC1
Parkinson Disease
Parkinson Disease - genetics
Parkinson's disease
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Summary: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.
ISSN:0197-4580
1558-1497
DOI:10.1016/j.neurobiolaging.2020.03.021