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Mitochondria function associated genes contribute to Parkinson’s Disease risk and later age at onset
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 functio...
Autores principales: | , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6531455/ https://www.ncbi.nlm.nih.gov/pubmed/31123700 http://dx.doi.org/10.1038/s41531-019-0080-x |
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author | Billingsley, Kimberley J. Barbosa, Ines A. Bandrés-Ciga, Sara Quinn, John P. Bubb, Vivien J. Deshpande, Charu Botia, Juan A. Reynolds, Regina H. Zhang, David Simpson, Michael A. Blauwendraat, Cornelis Gan-Or, Ziv Gibbs, J. Raphael Nalls, Mike A. Singleton, Andrew Ryten, Mina Koks, Sulev |
author_facet | Billingsley, Kimberley J. Barbosa, Ines A. Bandrés-Ciga, Sara Quinn, John P. Bubb, Vivien J. Deshpande, Charu Botia, Juan A. Reynolds, Regina H. Zhang, David Simpson, Michael A. Blauwendraat, Cornelis Gan-Or, Ziv Gibbs, J. Raphael Nalls, Mike A. Singleton, Andrew Ryten, Mina Koks, Sulev |
author_sort | Billingsley, Kimberley J. |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-6531455 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-65314552019-05-23 Mitochondria function associated genes contribute to Parkinson’s Disease risk and later age at onset Billingsley, Kimberley J. Barbosa, Ines A. Bandrés-Ciga, Sara Quinn, John P. Bubb, Vivien J. Deshpande, Charu Botia, Juan A. Reynolds, Regina H. Zhang, David Simpson, Michael A. Blauwendraat, Cornelis Gan-Or, Ziv Gibbs, J. Raphael Nalls, Mike A. Singleton, Andrew Ryten, Mina Koks, Sulev NPJ Parkinsons Dis Article 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. Nature Publishing Group UK 2019-05-22 /pmc/articles/PMC6531455/ /pubmed/31123700 http://dx.doi.org/10.1038/s41531-019-0080-x Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Billingsley, Kimberley J. Barbosa, Ines A. Bandrés-Ciga, Sara Quinn, John P. Bubb, Vivien J. Deshpande, Charu Botia, Juan A. Reynolds, Regina H. Zhang, David Simpson, Michael A. Blauwendraat, Cornelis Gan-Or, Ziv Gibbs, J. Raphael Nalls, Mike A. Singleton, Andrew Ryten, Mina Koks, Sulev Mitochondria function associated genes contribute to Parkinson’s Disease risk and later age at onset |
title | Mitochondria function associated genes contribute to Parkinson’s Disease risk and later age at onset |
title_full | Mitochondria function associated genes contribute to Parkinson’s Disease risk and later age at onset |
title_fullStr | Mitochondria function associated genes contribute to Parkinson’s Disease risk and later age at onset |
title_full_unstemmed | Mitochondria function associated genes contribute to Parkinson’s Disease risk and later age at onset |
title_short | Mitochondria function associated genes contribute to Parkinson’s Disease risk and later age at onset |
title_sort | mitochondria function associated genes contribute to parkinson’s disease risk and later age at onset |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6531455/ https://www.ncbi.nlm.nih.gov/pubmed/31123700 http://dx.doi.org/10.1038/s41531-019-0080-x |
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