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Journal Articles npj Parkinson's Disease Year : 2019

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

Kimberley J Billingsley (1) , Ines A Barbosa (2) , Sara Bandrés-Ciga (3) , John P Quinn (1) , Vivien J Bubb (1) , Charu Deshpande (4) , Juan A Botia (5, 6) , Regina H Reynolds (6) , David Zhang (6) , Michael A Simpson (2) , Cornelis Blauwendraat (3) , Ziv Gan-Or (7) , J. Raphael Gibbs (3) , Mike A Nalls (3) , Andrew Singleton (3) , A. Noyce , A. Tucci , B. Middlehurst , D. Kia , M. Tan , H. Houlden , H R Morris , H. Plun-Favreau , P. Holmans , J. Hardy , D. Trabzuni , J. Bras , K. Mok , K. Kinghorn , N. Wood , P. Lewis , R. Guerreiro , R. Lovering , L. R’bibo , M. Rizig , V. Escott-Price , V. Chelban , T. Foltynie , N. Williams , A. Brice (8) , F. Danjou (8) , S. Lesage (8) , M. Martinez , A. Giri , C. Schulte , K. Brockmann , J. Simón-Sánchez , P. Heutink , P. Rizzu , M. Sharma , T. Gasser , A. Nicolas , M. Cookson , F. Faghri , D. Hernandez , 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. Adarmes-Gómez , M. Aguilar , I. Alvarez , V. Alvarez , F. Javier Barrero , J. Bergareche Yarza , I. Bernal-Bernal , M. Blazquez , M. Bonilla-Toribio Bernal , M. Boungiorno , Dolores Buiza-Rueda , A. Cámara , M. Carcel , F. Carrillo , M. Carrión-Claro , D. Cerdan , J. Clarimón , Y. Compta , M. Diez-Fairen , O. Dols-Icardo , J. Duarte , R L Duran , F. Escamilla-Sevilla , M. Ezquerra , M. Fernández , R. Fernández-Santiago , C. Garcia , P. García-Ruiz , P. Gómez-Garre , M. Gomez Heredia , I. Gonzalez-Aramburu , A. Gorostidi Pagola , J. Hoenicka , J. Infante , S. Jesús , A. Jimenez-Escrig , J. Kulisevsky , M. Labrador-Espinosa , J. Lopez-Sendon , A. López de Munain Arregui , D. Macias , I. Martínez Torres , J. Marín , M. Jose Marti , J. Martínez-Castrillo , C. Méndez-Del-Barrio , M. Menéndez González , A. Mínguez , P. Mir , E. Mondragon Rezola , E. Muñoz , J. Pagonabarraga , P. Pastor , F. Perez Errazquin , T. Periñán-Tocino , J. Ruiz-Martínez , C. Ruz , A. Sanchez Rodriguez , M. Sierra , E. Suarez-Sanmartin , C. Tabernero , J. Pablo Tartari , C. Tejera-Parrado , E. Tolosa , F. Valldeoriola , L. Vargas-González , L. Vela , F. Vives , A. Zimprich , L. Pihlstrom , P. Taba , K. Majamaa , A. Siitonen , N. Okubadejo , O. Ojo , Mina Ryten (9) , Sulev Koks
A. Noyce
  • Function : Author
A. Tucci
  • Function : Author
B. Middlehurst
  • Function : Author
D. Kia
  • Function : Author
M. Tan
  • Function : Author
H. Houlden
  • Function : Author
H R Morris
  • Function : Author
H. Plun-Favreau
  • Function : Author
P. Holmans
  • Function : Author
J. Hardy
  • Function : Author
D. Trabzuni
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J. Bras
  • Function : Author
K. Mok
  • Function : Author
K. Kinghorn
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N. Wood
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P. Lewis
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R. Guerreiro
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R. Lovering
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L. R’bibo
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M. Rizig
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V. Escott-Price
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V. Chelban
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T. Foltynie
  • Function : Author
N. Williams
  • Function : Author
M. Martinez
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A. Giri
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C. Schulte
  • Function : Author
K. Brockmann
  • Function : Author
J. Simón-Sánchez
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P. Heutink
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P. Rizzu
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M. Sharma
  • Function : Author
T. Gasser
  • Function : Author
A. Nicolas
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M. Cookson
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F. Faghri
  • Function : Author
D. Hernandez
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J. Shulman
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L. Robak
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S. Lubbe
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S. Finkbeiner
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N. Mencacci
  • Function : Author
C. Lungu
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S. Scholz
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X. Reed
  • Function : Author
H. Leonard
  • Function : Author
G. Rouleau
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L. Krohan
  • Function : Author
J. van Hilten
  • Function : Author
J. Marinus
  • Function : Author
A. Adarmes-Gómez
  • Function : Author
M. Aguilar
  • Function : Author
I. Alvarez
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V. Alvarez
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F. Javier Barrero
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J. Bergareche Yarza
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I. Bernal-Bernal
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M. Blazquez
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M. Bonilla-Toribio Bernal
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M. Boungiorno
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Dolores Buiza-Rueda
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A. Cámara
  • Function : Author
M. Carcel
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F. Carrillo
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M. Carrión-Claro
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D. Cerdan
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J. Clarimón
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Y. Compta
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M. Diez-Fairen
  • Function : Author
O. Dols-Icardo
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J. Duarte
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R L Duran
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F. Escamilla-Sevilla
  • Function : Author
M. Ezquerra
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M. Fernández
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R. Fernández-Santiago
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C. Garcia
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P. García-Ruiz
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P. Gómez-Garre
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M. Gomez Heredia
  • Function : Author
I. Gonzalez-Aramburu
  • Function : Author
A. Gorostidi Pagola
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J. Hoenicka
  • Function : Author
J. Infante
  • Function : Author
S. Jesús
  • Function : Author
A. Jimenez-Escrig
  • Function : Author
J. Kulisevsky
  • Function : Author
M. Labrador-Espinosa
  • Function : Author
J. Lopez-Sendon
  • Function : Author
A. López de Munain Arregui
  • Function : Author
D. Macias
  • Function : Author
I. Martínez Torres
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J. Marín
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M. Jose Marti
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J. Martínez-Castrillo
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C. Méndez-Del-Barrio
  • Function : Author
M. Menéndez González
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A. Mínguez
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P. Mir
  • Function : Author
E. Mondragon Rezola
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E. Muñoz
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J. Pagonabarraga
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P. Pastor
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F. Perez Errazquin
  • Function : Author
T. Periñán-Tocino
  • Function : Author
J. Ruiz-Martínez
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C. Ruz
  • Function : Author
A. Sanchez Rodriguez
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M. Sierra
  • Function : Author
E. Suarez-Sanmartin
  • Function : Author
C. Tabernero
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J. Pablo Tartari
  • Function : Author
C. Tejera-Parrado
  • Function : Author
E. Tolosa
  • Function : Author
F. Valldeoriola
  • Function : Author
L. Vargas-González
  • Function : Author
L. Vela
  • Function : Author
F. Vives
  • Function : Author
A. Zimprich
  • Function : Author
L. Pihlstrom
  • Function : Author
P. Taba
  • Function : Author
K. Majamaa
  • Function : Author
A. Siitonen
  • Function : Author
N. Okubadejo
  • Function : Author
O. Ojo
  • Function : Author
Sulev Koks

Abstract

Abstract 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.
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Dates and versions

hal-04439714 , version 1 (05-02-2024)

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Kimberley J Billingsley, Ines A Barbosa, Sara Bandrés-Ciga, John P Quinn, Vivien J Bubb, et al.. Mitochondria function associated genes contribute to Parkinson’s Disease risk and later age at onset. npj Parkinson's Disease, 2019, 5 (1), pp.8. ⟨10.1038/s41531-019-0080-x⟩. ⟨hal-04439714⟩
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