SNCAandmTORPathway Single Nucleotide Polymorphisms Interact to Modulate the Age at Onset of Parkinson's Disease

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. © 2019 International Parkinson and Movement Disorder Society

Metal Exposure and SNCA rs356219 Polymorphism Associated With Parkinson Disease and Parkinsonism

“…Genome-wide association studies have demonstrated association between SNCA common variants and susceptibility to sporadic PD disease ( 54 ). In line with our findings, a recent meta-analysis showed that rs356219 is associated with increased risk of PD ( 55 ) (see ref in the comment field), while a recent study found that SNCA can modulate the PD age at onset ( 56 ).…”

Characterizing the genetic architecture of Parkinson’s disease in Latinos

“…A variant in RPS6KA2 was recently shown to be in an three-way epistatic relationship with a variant in SNCA and a variant in RPTOR in an age at PD onset study. 67 However, this admixture peak did not achieve significance in the joint test nor was the fine-mapped variant regionally significant ( see methods ). The mean proportion of African ancestry in LARGE-PD was under 0.06, meaning that we were underpowered to detect African-specific variation.…”

High Content Screening and Proteomic Analysis Identify a Kinase Inhibitor that rescues pathological phenotypes in a Patient-Derived Model of Parkinson’s Disease

“…6). Although the mechanistic link between αSyn and mTORC1 remains to be established, recent evidence shows that genetic variability in the mTOR pathway contributes to SNCA effects in disease pathogenesis [79].…”

“…Similarly, a quantitative proteomics study of a pre-symptomatic p.A53T-αSyn Drosophila model shows significant upregulation of ribosomal proteins in the p.A53T flies (71). Although the mechanistic link between p.A53T-αSyn and mTORC1 remains to be established, recent evidence shows that genetic variability in the mTOR pathway contributes to SNCA effects in disease pathogenesis (72).…”