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. 2019 Sep;34(9):1333-1344.
doi: 10.1002/mds.27770. Epub 2019 Jun 24.

SNCA and mTOR Pathway Single Nucleotide Polymorphisms Interact to Modulate the Age at Onset of Parkinson's Disease

Rubén Fernández-Santiago  1   2   3 , Núria Martín-Flores  4   5 , Francesca Antonelli  2 , Catalina Cerquera  2 , Verónica Moreno  2 , Sara Bandres-Ciga  6   7 , Elisabetta Manduchi  8 , Eduard Tolosa  1   2   3 , Andrew B Singleton  6 , Jason H Moore  8 ; International Parkinson's Disease Genomics Consortium; María-Josep Martí  1   2   3 , Mario Ezquerra  1   2   3 , Cristina Malagelada  4   5
Affiliations

SNCA and mTOR Pathway Single Nucleotide Polymorphisms Interact to Modulate the Age at Onset of Parkinson's Disease

Rubén Fernández-Santiago et al. Mov Disord. 2019 Sep.

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.

Keywords: Parkinson's disease; SNP; age at onset; alpha-synuclein; epistasis; mTOR.

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Conflict of interest statement

Relevant conflicts of interests/financial disclosures: Nothing to report.

References

    1. Fahn S Medical treatment of Parkinson’s disease. J Neurol 1998; 245(11 suppl 3):P15–P24. - PubMed
    1. Dauer W, Przedborski S. Parkinson’s disease: mechanisms and models. Neuron 2003;39(6):889–909. - PubMed
    1. Marras C, Lang A, van de Warrenburg BP, Sue CM, Tabrizi SJ, Bertram L, et al. Nomenclature of genetic movement disorders: Recommendations of the International Parkinson and Movement Disorder Society task force. Mov Disord 2017;32(5):724–725. - PubMed
    1. Pont-Sunyer C, Hotter A, Gaig C, Seppi K, Compta Y, Katzenschlager R, et al. The Onset of Nonmotor Symptoms in Parkinson’s disease (The ONSET PDStudy). Mov Disord 2015;30(2):229–237. - PubMed
    1. Nalls MA, Pankratz N, Lill CM, Do CB, Hernandez DG, Saad M, et al. Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson’s disease. Nat Genet 2014; 46(9):989–993. - PMC - PubMed

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