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Fernandez-Santiago, RubenAuthorAntonelli, FrancescaAuthorTolosa, EduardAuthorFernandez M.AuthorNoyce, Alastair JAuthorMarti MjAuthorTeresa Boungiorno, MariaAuthorFernandez, ManelAuthorEzquerra, MarioAuthor

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

Publicated to:Movement Disorders. 34 (9): 1333-1344 - 2019-09-01 34(9), DOI: 10.1002/mds.27770

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

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Abstract

Background Single nucleotide polymorphisms (SNPs) in the alpha-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. (c) 2019 International Parkinson and Movement Disorder Society

Keywords

alpha-synucleinassociationcomplexepistasismaptmodelsmtorparkinson's diseaseraptorreductionrisksnpvariantAge at onsetAlpha-synucleinAssociationComplexEpistasisMaptModelMtorNeuron deathParkinson's diseaseRaptorReductionRiskSnSnpVariant

Quality index

Bibliometric impact. Analysis of the contribution and dissemination channel

The work has been published in the journal Movement Disorders due to its progression and the good impact it has achieved in recent years, according to the agency WoS (JCR), it has become a reference in its field. In the year of publication of the work, 2019, it was in position 11/204, thus managing to position itself as a Q1 (Primer Cuartil), in the category Clinical Neurology. Notably, the journal is positioned above the 90th percentile.

From a relative perspective, and based on the normalized impact indicator calculated from the Field Citation Ratio (FCR) of the Dimensions source, it yields a value of: 6.35, which indicates that, compared to works in the same discipline and in the same year of publication, it ranks as a work cited above average. (source consulted: Dimensions Jun 2025)

Specifically, and according to different indexing agencies, this work has accumulated citations as of 2025-06-03, the following number of citations:

  • WoS: 20
  • Europe PMC: 10
  • Google Scholar: 24
  • OpenCitations: 20

Impact and social visibility

From the perspective of influence or social adoption, and based on metrics associated with mentions and interactions provided by agencies specializing in calculating the so-called "Alternative or Social Metrics," we can highlight as of 2025-06-03:

  • The use, from an academic perspective evidenced by the Altmetric agency indicator referring to aggregations made by the personal bibliographic manager Mendeley, gives us a total of: 63.
  • The use of this contribution in bookmarks, code forks, additions to favorite lists for recurrent reading, as well as general views, indicates that someone is using the publication as a basis for their current work. This may be a notable indicator of future more formal and academic citations. This claim is supported by the result of the "Capture" indicator, which yields a total of: 63 (PlumX).

With a more dissemination-oriented intent and targeting more general audiences, we can observe other more global scores such as:

  • The Total Score from Altmetric: 71.68.
  • The number of mentions on the social network X (formerly Twitter): 8 (Altmetric).

Leadership analysis of institutional authors

This work has been carried out with international collaboration, specifically with researchers from: Austria; Canada; Estonia; France; Germany; Israel; Netherlands; Norway; Saudi Arabia; United Kingdom; United States of America.

There is a significant leadership presence as some of the institution’s authors appear as the first or last signer, detailed as follows: First Author (Fernandez Santiago, Ruben) .