RT Journal Article
T1 SNCA and mTOR Pathway Single Nucleotide Polymorphisms Interact to Modulate the Age at Onset of Parkinson's Disease.
A1 Fernández-Santiago, Rubén
A1 Martín-Flores, Núria
A1 Antonelli, Francesca
A1 Cerquera, Catalina
A1 Moreno, Verónica
A1 Bandres-Ciga, Sara
A1 Manduchi, Elisabetta
A1 Tolosa, Eduard
A1 Singleton, Andrew B
A1 Moore, Jason H
A1 International Parkinson's Disease Genomics Consortium, 
A1 Martí, María-Josep
A1 Ezquerra, Mario
A1 Malagelada, Cristina
K1 Parkinson's disease
K1 SNP
K1 age at onset
K1 alpha-synuclein
K1 epistasis
K1 mTOR
AB 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.
YR 2019
FD 2019-06-24
LK http://hdl.handle.net/10668/14165
UL http://hdl.handle.net/10668/14165
LA en
DS RISalud
RD Apr 17, 2025