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Journal Articles Movement Disorders Year : 2019

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

Rubén Fernández-Santiago (1) , Núria Martín-Flores (2) , Francesca Antonelli , Catalina Cerquera , Verónica Moreno , Sara Bandres-Ciga (3, 4) , Elisabetta Manduchi (5) , Eduard Tolosa (1) , Andrew Singleton (3) , Jason Moore (5) , María-Josep Martí (1) , Mario Ezquerra (1) , Cristina Malagelada (2) , Alastair J Noyce , Rauan Kaiyrzhanov , Ben Middlehurst , Demis A Kia , Manuela Tan , Henry Houlden , Huw R Morris , Helene 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 (6) , Fabrice Danjou (6) , Suzanne Lesage (6) , Jean-Christophe Corvol (6) , Maria Martinez , Claudia Schulte , Kathrin Brockmann , Javier Simon-Sanchez , Peter Heutink , Patrizia Rizzu , Manu Sharma , Thomas Gasser , Aude Nicolas , Mark R. Cookson , Sara Bandres-Ciga , 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 , Andrew B. Singleton , 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 , Mario Ezquerra , Cici Feliz , Manel Fernández , Rubén Fernández- Santiago , 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 Munain Arregui , 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 , Eduard Tolosa , Francesc Valldeoriola , Laura Vargas- González , Lydia Vela , Francisco Vives , Alexander Zimprich , Lasse Pihlstrom , Mathias Toft , Sulev Koks , Pille Taba , Sharon Hassin-Baer
Francesca Antonelli
  • Function : Author
Catalina Cerquera
  • Function : Author
Verónica Moreno
  • Function : Author
Cristina Malagelada
Alastair J Noyce
  • Function : Author
Rauan Kaiyrzhanov
  • Function : Author
Ben Middlehurst
  • Function : Author
Demis A Kia
  • Function : Author
Manuela Tan
  • Function : Author
Henry Houlden
  • Function : Author
Huw R Morris
  • Function : Author
Helene Plun-Favreau
  • Function : Author
Peter Holmans
  • Function : Author
John Hardy
  • Function : Author
Daniah Trabzuni
  • Function : Author
Jose Bras
  • Function : Author
John Quinn
  • Function : Author
Kin Y. Mok
  • Function : Author
Kerri J. Kinghorn
  • Function : Author
Kimberley Billingsley
  • Function : Author
Nicholas W. Wood
  • Function : Author
Patrick Lewis
  • Function : Author
Sebastian Schreglmann
  • Function : Author
Rita Guerreiro
  • Function : Author
Ruth Lovering
  • Function : Author
Lea R’bibo
  • Function : Author
Claudia Manzoni
  • Function : Author
Mie Rizig
  • Function : Author
Mina Ryten
  • Function : Author
Sebastian Guelfi
  • Function : Author
Valentina Escott-Price
  • Function : Author
Viorica Chelban
  • Function : Author
Thomas Foltynie
  • Function : Author
Nigel Williams
  • Function : Author
Karen E. Morrison
  • Function : Author
Carl Clarke
  • Function : Author
Maria Martinez
  • Function : Author
Claudia Schulte
  • Function : Author
Kathrin Brockmann
  • Function : Author
Javier Simon-Sanchez
  • Function : Author
Peter Heutink
  • Function : Author
Patrizia Rizzu
  • Function : Author
Manu Sharma
  • Function : Author
Thomas Gasser
  • Function : Author
Aude Nicolas
  • Function : Author
Mark R. Cookson
  • Function : Author
Sara Bandres-Ciga
  • Function : Author
Cornelis Blauwendraat
  • Function : Author
David W. Craig
  • Function : Author
Faraz Faghri
  • Function : Author
J. Raphael Gibbs
  • Function : Author
Dena G. Hernandez
  • Function : Author
Kendall Van Keuren-Jensen
  • Function : Author
Joshua M. Shulman
  • Function : Author
Hirotaka Iwaki
  • Function : Author
Hampton L. Leonard
  • Function : Author
Mike A. Nalls
  • Function : Author
Laurie Robak
  • Function : Author
Steven Lubbe
  • Function : Author
Steven Finkbeiner
  • Function : Author
Niccolo E. Mencacci
  • Function : Author
Codrin Lungu
  • Function : Author
Andrew B. Singleton
  • Function : Author
Sonja W. Scholz
  • Function : Author
Xylena Reed
  • Function : Author
Roy N. Alcalay
  • Function : Author
Ziv Gan-Or
  • Function : Author
Guy A. Rouleau
  • Function : Author
Lynne Krohn
  • Function : Author
Jacobus J. Van Hilten
  • Function : Author
Johan Marinus
  • Function : Author
Astrid D. Adarmes-Gómez
  • Function : Author
Iquel Aguilar
  • Function : Author
Ignacio Alvarez
  • Function : Author
Victoria Alvarez
  • Function : Author
Francisco Javier Barrero
  • Function : Author
Inmaculada Bernal-Bernal
  • Function : Author
Marta Blazquez
  • Function : Author
Marta Bonilla-Toribio
  • Function : Author
Juan A. Botía
  • Function : Author
María Teresa Boungiorno
  • Function : Author
Dolores Buiza-Rueda
  • Function : Author
Ana Cámara
  • Function : Author
Fátima Carrillo
  • Function : Author
Mario Carrión-Claro
  • Function : Author
Debora Cerdan
  • Function : Author
Jordi Clarimón
  • Function : Author
Yaroslau Compta
  • Function : Author
Beatriz de La Casa
  • Function : Author
Monica Diez-Fairen
  • Function : Author
Oriol Dols-Icardo
  • Function : Author
Jacinto Duarte
  • Function : Author
Raquel Duran
  • Function : Author
Francisco Escamilla-Sevilla
  • Function : Author
Mario Ezquerra
  • Function : Author
Cici Feliz
  • Function : Author
Manel Fernández
  • Function : Author
Rubén Fernández- Santiago
  • Function : Author
Ciara Garcia
  • Function : Author
Pedro García-Ruiz
  • Function : Author
Pilar Gómez-Garre
  • Function : Author
Maria Jose Gomez Heredia
  • Function : Author
Isabel Gonzalez-Aramburu
  • Function : Author
Ana Gorostidi Pagola
  • Function : Author
Janet Hoenicka
  • Function : Author
Jon Infante
  • Function : Author
Silvia Jesús
  • Function : Author
Adriano Jimenez-Escrig
  • Function : Author
Jaime Kulisevsky
  • Function : Author
Miguel A. Labrador-Espinosa
  • Function : Author
Jose Luis Lopez-Sendon
  • Function : Author
Daniel Macias
  • Function : Author
Irene Martínez Torres
  • Function : Author
Juan Marín
  • Function : Author
Maria Jose Marti
  • Function : Author
Carlota Méndez-Del-Barrio
  • Function : Author
Manuel Menéndez González
  • Function : Author
Marina Mata
  • Function : Author
Adolfo Mínguez
  • Function : Author
Pablo Mir
  • Function : Author
Elisabet Mondragon Rezola
  • Function : Author
Esteban Muñoz
  • Function : Author
Javier Pagonabarraga
  • Function : Author
Berta Pascual-Sedano
  • Function : Author
Pau Pastor
  • Function : Author
Francisco Perez Errazquin
  • Function : Author
Teresa Periñán-Tocino
  • Function : Author
Javier Ruiz- Martínez
  • Function : Author
Clara Ruz
  • Function : Author
Antonio Sanchez Rodriguez
  • Function : Author
María Sierra
  • Function : Author
Esther Suarez-Sanmartin
  • Function : Author
Cesar Tabernero
  • Function : Author
Juan Pablo Tartari
  • Function : Author
Cristina Tejera-Parrado
  • Function : Author
Eduard Tolosa
  • Function : Author
Francesc Valldeoriola
  • Function : Author
Laura Vargas- González
  • Function : Author
Lydia Vela
  • Function : Author
Francisco Vives
  • Function : Author
Alexander Zimprich
  • Function : Author
Lasse Pihlstrom
  • Function : Author
Mathias Toft
  • Function : Author
Sulev Koks
  • Function : Author
Pille Taba
  • Function : Author
Sharon Hassin-Baer
  • Function : Author

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.

Dates and versions

hal-04560057 , version 1 (26-04-2024)

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Cite

Rubén Fernández-Santiago, Núria Martín-Flores, Francesca Antonelli, Catalina Cerquera, Verónica Moreno, et al.. SNCA and mTOR Pathway Single Nucleotide Polymorphisms Interact to Modulate the Age at Onset of Parkinson's Disease. Movement Disorders, 2019, 34 (9), pp.1333-1344. ⟨10.1002/mds.27770⟩. ⟨hal-04560057⟩
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