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

Rubén Fernández-Santiago, Núria Martín-Flores, Francesca Antonelli, Catalina Cerquera, Verónica Moreno, Sara Bandres-Ciga, Elisabetta Manduchi, Eduard Tolosa, Andrew B. Singleton, Jason H. Moore, María Josep Martí, Mario Ezquerra, Cristina Malagelada*, Alastair J. Noyce, Rauan Kaiyrzhanov, Ben Middlehurst, Demis A. Kia, Manuela Tan, Henry Houlden, Huw R. MorrisHelene Plun-Favreau, Peter Holmans, John Hardy, Daniah Trabzuni, Jose Bras, John Quinn, Kin Y. Mok, Kerri J. Kinghorn, Kimberley Billingsley, Nicholas W. Wood, Patrick Lewis, Sebastian Schreglmann, Rita Guerreiro, Ruth Lovering, Lea R’Bibo, Claudia Manzoni, Mie Rizig, Mina Ryten, Sebastian Guelfi, Valentina Escott-Price, Viorica Chelban, Thomas Foltynie, Nigel Williams, Karen E. Morrison, Carl Clarke, Alexis Brice, Fabrice Danjou, Suzanne Lesage, Jean Christophe Corvol, Maria Martinez, Claudia Schulte, Kathrin Brockmann, Javier Simon-Sanchez, Peter Heutink, Patrizia Rizzu, Manu Sharma, Thomas Gasser, Aude Nicolas, Mark R. Cookson, Cornelis Blauwendraat, David W. Craig, Faraz Faghri, J. Raphael Gibbs, Dena G. Hernandez, Kendall Van Keuren-Jensen, Joshua M. Shulman, Hirotaka Iwaki, Hampton L. Leonard, Mike A. Nalls, Laurie Robak, Steven Lubbe, Steven Finkbeiner, Niccolo E. Mencacci, Codrin Lungu, Sonja W. Scholz, Xylena Reed, Roy N. Alcalay, Ziv Gan-Or, Guy A. Rouleau, Lynne Krohn, Jacobus J. Van Hilten, Johan Marinus, Astrid D. Adarmes-Gómez, Iquel Aguilar, Ignacio Alvarez, Victoria Alvarez, Francisco Javier Barrero, Jesús Alberto Bergareche Yarza, Inmaculada Bernal-Bernal, Marta Blazquez, Marta Bonilla-Toribio, Juan A. Botía, María Teresa Boungiorno, Dolores Buiza-Rueda, Ana Cámara, Fátima Carrillo, Mario Carrión-Claro, Debora Cerdan, Jordi Clarimón, Yaroslau Compta, Beatriz De La Casa, Monica Diez-Fairen, Oriol Dols-Icardo, Jacinto Duarte, Raquel Duran, Francisco Escamilla-Sevilla, Cici Feliz, Manel Fernández, Ciara Garcia, Pedro García-Ruiz, Pilar Gómez-Garre, Maria Jose Gomez Heredia, Isabel Gonzalez-Aramburu, Ana Gorostidi Pagola, Janet Hoenicka, Jon Infante, Silvia Jesús, Adriano Jimenez-Escrig, Jaime Kulisevsky, Miguel A. Labrador-Espinosa, Jose Luis Lopez-Sendon, Adolfo López De Munainarregui, Daniel Macias, Irene Martínez Torres, Juan Marín, Maria Jose Marti, Juan Carlos Mar-Tínez-castrillo, Carlota Méndez-Del-barrio, Manuel Menéndez González, Marina Mata, Adolfo Mínguez, Pablo Mir, Elisabet Mondragon Rezola, Esteban Muñoz, Javier Pagonabarraga, Berta Pascual-Sedano, Pau Pastor, Francisco Perez Errazquin, Teresa Periñán-Tocino, Javier Ruiz-Martínez, Clara Ruz, Antonio Sanchez Rodriguez, María Sierra, Esther Suarez-Sanmartin, Cesar Tabernero, Juan Pablo Tartari, Cristina Tejera-Parrado, Francesc Valldeoriola, Laura Vargas-González, Lydia Vela, Francisco Vives, Alexander Zimprich, Lasse Pihlstrom, Mathias Toft, Sulev Koks, Pille Taba, Sharon Hassin-Baer

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

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 languageEnglish (US)
Pages (from-to)1333-1344
Number of pages12
JournalMovement Disorders
Volume34
Issue number9
DOIs
StatePublished - Sep 1 2019

Keywords

  • Parkinson's disease
  • SNP
  • age at onset
  • alpha-synuclein
  • epistasis
  • mTOR

ASJC Scopus subject areas

  • Clinical Neurology
  • Neurology

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