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 Singleton; Jason Moore; María-Josep Martí; Mario Ezquerra; Cristina Malagelada; 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; 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; 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

doi:10.1002/mds.27770

Journal Articles Movement Disorders Year : 2019

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

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Rubén Fernández-Santiago

Function : Author

Institut d'Investigacions Biomèdiques August Pi i Sunyer

Núria Martín-Flores

Function : Author

Universitat de Barcelona

Francesca Antonelli

Function : Author

Catalina Cerquera

Function : Author

Verónica Moreno

Function : Author

Sara Bandres-Ciga

Function : Author

National Institute on Aging [Bethesda, USA]

ibs.GRANADA Instituto de Investigación Biosanitaria [Granada, Spain]

Elisabetta Manduchi

Function : Author

Perelman School of Medicine

Eduard Tolosa

Function : Author

Institut d'Investigacions Biomèdiques August Pi i Sunyer

Andrew Singleton

Function : Author

National Institute on Aging [Bethesda, USA]

Jason Moore

Function : Author

Perelman School of Medicine

María-Josep Martí

Function : Author

Institut d'Investigacions Biomèdiques August Pi i Sunyer

Mario Ezquerra

Function : Author

Institut d'Investigacions Biomèdiques August Pi i Sunyer

Cristina Malagelada

Function : Author
PersonId : 1378418
ORCID : 0000-0001-7185-436X

Universitat de Barcelona

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

Alexis Brice

Function : Author
PersonId : 1104774
ORCID : 0000-0002-0941-3990
IdRef : 050512935

Institut du Cerveau = Paris Brain Institute

Fabrice Danjou

Function : Author

Institut du Cerveau = Paris Brain Institute

Suzanne Lesage

Function : Author

Institut du Cerveau = Paris Brain Institute

Jean-Christophe Corvol

Function : Author

Institut du Cerveau = Paris Brain Institute

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

Jesús Alberto Bergareche Yarza

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

Adolfo López de Munain Arregui

Function : Author

Daniel Macias

Function : Author

Irene Martínez Torres

Function : Author

Juan Marín

Function : Author

Maria Jose Marti

Function : Author

Juan Carlos Mar- Tínez-Castrillo

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.

Keywords

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

Domains

Life Sciences [q-bio]

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https://hal.sorbonne-universite.fr/hal-04560057

Submitted on : Friday, April 26, 2024-9:26:51 AM

Last modification on : Monday, July 8, 2024-4:11:09 PM

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

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HAL Id : hal-04560057 , version 1
DOI : 10.1002/mds.27770
PUBMED : 31234232
PUBMEDCENTRAL : PMC7322732

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

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