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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
medicine
SNCA and mTOR Pathway Single Nucleotide Polymorphisms Interact to Modulate the Age at Onset of Parkinson's Disease
Movement Disorders, Volume 34, No. 9, Year 2019
Notification
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Description
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.
Authors & Co-Authors
Fernández-Santiago, Rubén
Spain, Barcelona
Institut D'investigacions Biomèdiques August pi I Sunyer - Idibaps
Spain, Barcelona
Hospital Clinic Barcelona
Spain, Madrid
Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas
Martín-Flores, Nuria
Spain, Barcelona
Universitat de Barcelona
Antonelli, Francesca
Spain, Barcelona
Hospital Clinic Barcelona
Cerquera-Cleves, Catalina
Spain, Barcelona
Hospital Clinic Barcelona
Colombia, Bogota
Hospital Universitario San Ignacio
Moreno, Verónica
Spain, Barcelona
Hospital Clinic Barcelona
Bandres-Ciga, Sara
United States, Bethesda
National Institute on Aging Nia
Spain, Granada
Instituto de Investigación Biosanitaria de Granada Ibs.granada
Manduchi, Elisabetta
United States, Philadelphia
University of Pennsylvania Perelman School of Medicine
Tolosa, Eduardo S.
Spain, Barcelona
Institut D'investigacions Biomèdiques August pi I Sunyer - Idibaps
Spain, Barcelona
Hospital Clinic Barcelona
Spain, Madrid
Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas
Singleton, Andrew B.
United States, Bethesda
National Institute on Aging Nia
Moore, Jason H.
United States, Philadelphia
University of Pennsylvania Perelman School of Medicine
Martí, Maria Josep
Spain, Barcelona
Institut D'investigacions Biomèdiques August pi I Sunyer - Idibaps
Spain, Barcelona
Hospital Clinic Barcelona
Spain, Madrid
Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas
Ezquerra, Mario
Spain, Barcelona
Institut D'investigacions Biomèdiques August pi I Sunyer - Idibaps
Spain, Barcelona
Hospital Clinic Barcelona
Spain, Madrid
Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas
Malagelada, Cristina
Spain, Barcelona
Universitat de Barcelona
Noyce, Alastair John
United Kingdom, London
Barts and the London School of Medicine and Dentistry
United Kingdom, London
University College London
Kaiyrzhanov, Rauan
United Kingdom, London
Ucl Queen Square Institute of Neurology
Middlehurst, Ben
United Kingdom, Liverpool
University of Liverpool
Kia, Demis A.
United Kingdom, London
Ucl Queen Square Institute of Neurology
Tan, Manuela M.X.
United Kingdom, London
University College London
Houlden, Henry H.
United Kingdom, London
Ucl Queen Square Institute of Neurology
Morris, Huw R.
United Kingdom, London
University College London
Plun-Favreau, Hélène
United Kingdom, London
Ucl Queen Square Institute of Neurology
Holmans, Peter A.
United Kingdom, Cardiff
Mrc Centre for Neuropsychiatric Genetics and Genomics
Hardy, John A.
United Kingdom, London
Ucl Queen Square Institute of Neurology
Trabzuni, Daniah
United Kingdom, London
Ucl Queen Square Institute of Neurology
Saudi Arabia, Riyadh
King Faisal Specialist Hospital and Research Centre
Brás, José Miguel
United Kingdom, London
Ucl Queen Square Institute of Neurology
Quinn, John P.
United Kingdom, Liverpool
University of Liverpool
Mok, Kin Y.
United Kingdom, London
Ucl Queen Square Institute of Neurology
Kinghorn, Kerri J.
United Kingdom, London
University College London
Billingsley, Kimberley J.
United Kingdom, Liverpool
University of Liverpool
Wood, Nick William
United Kingdom, London
Ucl Queen Square Institute of Neurology
Lewis, Patrick Alfryn
United Kingdom, Reading
University of Reading
Schreglmann, Sebastian R.
United Kingdom, London
Ucl Queen Square Institute of Neurology
Guerreiro, Rita João
United Kingdom, London
Ucl Queen Square Institute of Neurology
Lovering, Ruth C.
United Kingdom, London
University College London
R’Bibo, Lea
United Kingdom, London
Ucl Queen Square Institute of Neurology
Manzoni, Claudia
United Kingdom, Reading
University of Reading
Rizig, Mie A.
United Kingdom, London
Ucl Queen Square Institute of Neurology
Ryten, Mina
United Kingdom, London
Ucl Queen Square Institute of Neurology
Guelfi, Sebastian
United Kingdom, London
Ucl Queen Square Institute of Neurology
Escott-Price, Valentina
United Kingdom, Cardiff
Cardiff University School of Medicine
Chelban, Viorica
United Kingdom, London
Ucl Queen Square Institute of Neurology
Foltynie, Thomas
United Kingdom, London
Ucl Queen Square Institute of Neurology
Williams, Nigel M.
United Kingdom, Cardiff
Mrc Centre for Neuropsychiatric Genetics and Genomics
Morrison, Karen E.
United Kingdom, Southampton
University of Southampton, Faculty of Medicine
Clarke, Carl E.
United Kingdom, Birmingham
University of Birmingham
United Kingdom, West Bromwich
Sandwell and West Birmingham Hospitals Nhs Trust
Brice, Alexis
France, Paris
Sorbonne Université
Danjou, Fabrice
France, Paris
Sorbonne Université
Lesage, Suzanne
France, Paris
Sorbonne Université
Corvol, Jean Christophe
France, Paris
Sorbonne Université
Martinez, Maria M.
France, Toulouse
Université Toulouse Iii - Paul Sabatier
Schulte, Claudia M.S.
Germany, Tubingen
Hertie-institut Für Klinische Hirnforschung
Brockmann, Kathrin
Germany, Tubingen
Hertie-institut Für Klinische Hirnforschung
Simón-Sánchez, Javier
Germany, Tubingen
Hertie-institut Für Klinische Hirnforschung
Heutink, Peter
Germany, Tubingen
Hertie-institut Für Klinische Hirnforschung
Rizzu, Patrizia
Germany, Bonn
Deutsches Zentrum Für Neurodegenerative Erkrankungen
Sharma, Manu
Germany, Tubingen
Eberhard Karls Universität Tübingen
Gasser, Thomas
Germany, Bonn
Deutsches Zentrum Für Neurodegenerative Erkrankungen
Nicolas, Aude
United States, Bethesda
National Institute on Aging Nia
Cookson, Mark Robert
United States, Bethesda
National Institute on Aging Nia
Blauwendraat, Cornelis
United States, Bethesda
National Institute of Neurological Disorders and Stroke
Craig, David Wesley
United States, Los Angeles
Keck School of Medicine of Usc
Faghri, Faraz
United States, Bethesda
National Institute on Aging Nia
United States, Urbana
University of Illinois Urbana-champaign
Gibbs, J. Raphael
United States, Bethesda
National Institute on Aging Nia
Hernandez, Dena G.
United States, Bethesda
National Institute on Aging Nia
Van Keuren-Jensen, Kendall R.
United States, Phoenix
Translational Genomics Research Institute
Shulman, Joshua M.
United States, Houston
Baylor College of Medicine
United States, Houston
Texas Children's Hospital
Iwaki, Hirotaka
United States, Bethesda
National Institute on Aging Nia
Leonard, Hampton L.
United States, Bethesda
National Institute on Aging Nia
Nalls, Mike A.
United States, Bethesda
National Institute on Aging Nia
United States, Glen Echo
Data Tecnica International
Robak, Laurie A.
United States, Houston
Baylor College of Medicine
Lubbe, Steven J.
United States, Chicago
Northwestern University Feinberg School of Medicine
Finkbeiner, Steven M.
United States, San Francisco
University of California, San Francisco
United States, San Francisco
Gladstone Institute of Neurological Disease
Mencacci, Niccolò Emanuele
United States, Chicago
Northwestern University Feinberg School of Medicine
Lungu, Codrin I.
United States, Bethesda
National Institute of Neurological Disorders and Stroke
Scholz, Sonja W.
United States, Bethesda
National Institute of Neurological Disorders and Stroke
Reed, Xylena
United States, Bethesda
National Institute on Aging Nia
Alcalay, Roy N.
United States, New York
Vagelos College of Physicians and Surgeons
Gan-Or, Ziv
Canada, Montreal
Institut-hôpital Neurologique de Montréal
Rouleau, Guy Armand
Canada, Montreal
Institut-hôpital Neurologique de Montréal
Krohn, Lynne
Canada, Montreal
Institut-hôpital Neurologique de Montréal
van Hilten, Jacobus Johannes Bob
Netherlands, Leiden
Leids Universitair Medisch Centrum
Marinus, Johan
Netherlands, Leiden
Leids Universitair Medisch Centrum
Adarmes-GɃmez, Astrid D.
Spain, Sevilla
Hospital Universitario Virgen Del Rocío
Aguilar, Iquel
Spain, Terrassa
Mutua de Terrassa
Alvarez, Ignacio
Spain, Terrassa
Mutua de Terrassa
Alvarez, Victoria
Spain, Oviedo
Hospital Universitario Central de Asturias
Barrero, Francisco Javier
Spain, Granada
Hospital Universitario San Cecilio
Bergareche Yarza, Jesús Alberto
Spain, Donostia-san Sebastian
Biodonostia Health Research Institute
Bernal-Bernal, Inmaculada
Spain, Sevilla
Hospital Universitario Virgen Del Rocío
Blázquez Estrada, Marta
Spain, Oviedo
Hospital Universitario Central de Asturias
Bonilla-Toribio, Marta
Spain, Sevilla
Hospital Universitario Virgen Del Rocío
Botia, Juan A.
Spain, Terrassa
Mutua de Terrassa
Boungiorno, María Teresa
Spain, Terrassa
Mutua de Terrassa
Buiza-Rueda, Dolores
Spain, Sevilla
Hospital Universitario Virgen Del Rocío
Cámara, Ana
Spain, Barcelona
Hospital Clinic Barcelona
Carrillo, Fátima
Spain, Sevilla
Hospital Universitario Virgen Del Rocío
Carrion-Claro, Mario
Spain, Sevilla
Hospital Universitario Virgen Del Rocío
Cerdán, Débora María
Spain, Segovia
Hospital General de Segovia
Clarimón, Jordi
Spain, Barcelona
Hospital de la Santa Creu I Sant Pau
Compta, Yaroslau
Spain, Barcelona
Hospital Clinic Barcelona
Statistics
Citations: 100
Authors: 100
Affiliations: 44
Identifiers
Doi:
10.1002/mds.27770
ISSN:
08853185
e-ISSN:
15318257
Research Areas
Cancer
Genetics And Genomics
Study Design
Cohort Study
Case-Control Study