Abstract
Background: 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. Objectives: 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. Methods: 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. Results: 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 <.001). In addition, we also found a 3-loci epistatic combination of RPTOR rs11868112 and RPS6KA2 rs6456121 with SNCA rs356219, which was associated (odds ratio = 2.89; P <.0001) with differential AAO. The latter was further validated (odds ratio = 1.56; P = 0.046-0.047) in the International Parkinson's Disease Genomics Consortium cohort. Conclusions: 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.
Original language | English (US) |
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Pages (from-to) | 1333-1344 |
Number of pages | 12 |
Journal | Movement Disorders |
Volume | 34 |
Issue number | 9 |
DOIs | |
State | Published - Sep 1 2019 |
Funding
We thank Dr. Peter Andrews for this kind assessment with the multifactor dimensionality reduction (MDR) software use and helpful discussion. We also thank Dr. Roger Anglada from the Genomics Core Facility from the Universitat Pompeu Fabra (Barcelona) for his work and helpful assessment with sample analysis. We acknowledge the Centres de Recerca de Catalunya (CERCA) Program from the Generalitat de Catalunya and the Fondo Europeo de Desarrollo Regional (FEDER) Program from the European Union to Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS). RF-S was supported by a Jóvenes Investigadores grant (SAF2015-73508-JIN) through the Programa Estatal de Investigación, Desarrollo e Innovación Orientada a los Retos de la Sociedad (Plan Estatal de Investigacion Cientifica, tecnica y de innovacion (ICDCI) 2013–2016) of the Spanish Ministry of Economy and Competitiveness Ministerio de Economia (MINECO), and the Agencia Estatal de Investigación, which is cofunded by FEDER Agencia Europea de Investigacion/Fondo Europeo de Desarrollo Regional/Union Europea (AEI/FEDER/UE).
Keywords
- Parkinson's disease
- SNP
- age at onset
- alpha-synuclein
- epistasis
- mTOR
ASJC Scopus subject areas
- Neurology
- Clinical Neurology