AbstractBackgroundSingle 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.ObjectivesThe mechanistic target of rapamycin (mTOR) signaling pathway is functionally impaired in PD. Here we explored whether SNPs in themTORpathway, alone or by epistatic interaction with known susceptibility factors, can modulate PD risk and AAO.MethodsBased on functional relevance, we selected a total of 64 SNPs mapping to a total of 57 genes from themTORpathway 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.ResultsIn the discovery series cohort, we found a 4‐loci interaction involvingSTK11rs8111699,FCHSD1rs456998,GSK3Brs1732170, andSNCArs356219, 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 ofRPTORrs11868112 andRPS6KA2rs6456121 withSNCArs356219, 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.ConclusionsThese findings indicate that genetic variability in themTORpathway contributes toSNCAeffects 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