Mitochondria function associated genes contribute to Parkinson's Disease risk and later age at onset

Jaime Kulisevsky, K. J. Billingsley, I. A. Barbosa, S. Bandrés-Ciga, J. P. Quinn, Vivien Bubb, C. Deshpande, J. A. Botia, R. H. Reynolds, D. Zhang, M. A. Simpson, Cornelis Blauwendraat, Z. Gan-Or, J. R. Gibbs, M. A. Nalls, A. Singleton, A. Noyce, A. Tucci, B. Middlehurst, Demis A KiaM. Tan, Henry Houlden, H. R. Morris, H. Plun-Favreau, Peter Holmans, J. Hardy, D. Trabzuni, J. Bras, K. Mok, K. Kinghorn, N. Wood, P. Lewis, Rita Guerreiro, R. Lovering, L. R'Bibo, M. Rizig, Valentina Escott-Price, Viorica Chelban, T. Foltynie, N. Williams, Alexis Brice, F. Danjou, S. Lesage, M. Martinez, A. Giri, C. Schulte, K. Brockmann, J. Simón-Sánchez, Peter Heutink, P. Rizzu, M. Sharma, Thomas Gasser, A. Nicolas, M. R Cookson, F. Faghri, Dena Hernández, J. Shulman, L. Robak, S. Lubbe, S. Finkbeiner, N. Mencacci, C. Lungu, S. Scholz, X. Reed, H. Leonard, G. Rouleau, L. Krohan, J. van Hilten, J. Marinus, A.D Adarmes-Gómez, Miquel Aguilar Barberà, Ignacio Alvarez, V. Alvarez, F. Javier Barrero, J. Bergareche Yarza, I. Bernal-Bernal, Marta Blázquez Estrada, M. B. T. Bernal, M. T Boungiorno, Dolores Buiza-Rueda, Ana Cámara, M. Carcel, F. Carrillo, M. Carrión-Claro, Debora Cerdan, Jordi Clarimón, Yaroslau Compta, Monica. Diez-Fairen, Oriol Dols Icardo, J. Duarte, Raquel Duran, F. Escamilla-Sevilla, M. Ezquerra, M. Fernández, Rubén Fernández-Santiago, C.. Garcia, P. García-Ruiz, P. Gómez-Garre, M. G. Heredia, Isabel Gonzalez-Aramburu, A. G. Pagola, J. Hoenicka, J. Infante, S. Jesús, A. Jimenez-Escrig, Miguel A Labrador-Espinosa, J. Lopez-Sendon, A. L. de Munain Arregui, Daniel Macías-García, I. M. Torres, J. Marín, M. J. Marti, J. Martínez-Castrillo, C. Méndez-del-Barrio, M. Menéndez González, A. Mínguez, P. Mir, E. M. Rezola, José Esteban Muñoz García, Javier Pagonabarraga Mora, Pau Pastor, F. P. Errazquin, T. Periñán-Tocino, J. Ruiz-Martínez, C. Ruz, A. S. Rodriguez, M. Sierra, E. Suarez-Sanmartin, C. Tabernero, J. P. Tartari, C. Tejera-Parrado, E. Tolosa, F. Valldeoriola, L. Vargas-González, Lydia Vela, F. Vives, Alexander Zimprich, L. Pihlstrom, P. Taba, K. Majamaa, A. Siitonen, N. Okubadejo, O. Ojo, Mina Ryten, S. Koks

Producció científica: Contribució a revistaArticleRecercaAvaluat per experts

97 Cites (Scopus)

Resum

Mitochondrial dysfunction has been implicated in the etiology of monogenic Parkinson's disease (PD). Yet the role that mitochondrial processes play in the most common form of the disease; sporadic PD, is yet to be fully established. Here, we comprehensively assessed the role of mitochondrial function-associated genes in sporadic PD by leveraging improvements in the scale and analysis of PD GWAS data with recent advances in our understanding of the genetics of mitochondrial disease. We calculated a mitochondrial-specific polygenic risk score (PRS) and showed that cumulative small effect variants within both our primary and secondary gene lists are significantly associated with increased PD risk. We further reported that the PRS of the secondary mitochondrial gene list was significantly associated with later age at onset. Finally, to identify possible functional genomic associations we implemented Mendelian randomization, which showed that 14 of these mitochondrial function-associated genes showed functional consequence associated with PD risk. Further analysis suggested that the 14 identified genes are not only involved in mitophagy, but implicate new mitochondrial processes. Our data suggests that therapeutics targeting mitochondrial bioenergetics and proteostasis pathways distinct from mitophagy could be beneficial to treating the early stage of PD.
Idioma originalAnglès
Revistanpj Parkinson's Disease
Volum5
Número1
DOIs
Estat de la publicacióPublicada - 2019

Fingerprint

Navegar pels temes de recerca de 'Mitochondria function associated genes contribute to Parkinson's Disease risk and later age at onset'. Junts formen un fingerprint únic.

Com citar-ho