Publication: SNCA and mTOR Pathway Single Nucleotide Polymorphisms Interact to Modulate the Age at Onset of Parkinson's Disease.
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Date
2019-06-24
Authors
Fernández-Santiago, Rubén
Martín-Flores, Núria
Antonelli, Francesca
Cerquera, Catalina
Moreno, Verónica
Bandres-Ciga, Sara
Manduchi, Elisabetta
Tolosa, Eduard
Singleton, Andrew B
Moore, Jason H
Advisors
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Abstract
Single nucleotide polymorphisms (SNPs) in the α-synuclein (SNCA) gene are associated with differential risk and age at onset (AAO) of both idiopathic and Leucine-rich repeat kinase 2 (LRRK2)-associated Parkinson's disease (PD). Yet potential combinatory or synergistic effects among several modulatory SNPs for PD risk or AAO remain largely underexplored. The mechanistic target of rapamycin (mTOR) signaling pathway is functionally impaired in PD. Here we explored whether SNPs in the mTOR pathway, alone or by epistatic interaction with known susceptibility factors, can modulate PD risk and AAO. Based on functional relevance, we selected a total of 64 SNPs mapping to a total of 57 genes from the mTOR pathway and genotyped a discovery series cohort encompassing 898 PD patients and 921 controls. As a replication series, we screened 4170 PD and 3014 controls available from the International Parkinson's Disease Genomics Consortium. In the discovery series cohort, we found a 4-loci interaction involving STK11 rs8111699, FCHSD1 rs456998, GSK3B rs1732170, and SNCA rs356219, which was associated with an increased risk of PD (odds ratio = 2.59, P These findings indicate that genetic variability in the mTOR pathway contributes to SNCA effects in a nonlinear epistatic manner to modulate differential AAO in PD, unraveling the contribution of this cascade in the pathogenesis of the disease. © 2019 International Parkinson and Movement Disorder Society.
Description
MeSH Terms
Adult
Age of Onset
Aged
Aged, 80 and over
Chromosome Mapping
Cohort Studies
Epistasis, Genetic
Female
Genetic Predisposition to Disease
Genotype
Humans
Male
Middle Aged
Parkinson Disease
Polymorphism, Single Nucleotide
Risk Assessment
Signal Transduction
TOR Serine-Threonine Kinases
alpha-Synuclein
Age of Onset
Aged
Aged, 80 and over
Chromosome Mapping
Cohort Studies
Epistasis, Genetic
Female
Genetic Predisposition to Disease
Genotype
Humans
Male
Middle Aged
Parkinson Disease
Polymorphism, Single Nucleotide
Risk Assessment
Signal Transduction
TOR Serine-Threonine Kinases
alpha-Synuclein
DeCS Terms
CIE Terms
Keywords
Parkinson's disease, SNP, age at onset, alpha-synuclein, epistasis, mTOR