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



Billingsley, Kimberley J, Barbosa, Ines A, Bandres-Ciga, Sara, Quinn, John P ORCID: 0000-0003-3551-7803, Bubb, Vivien J ORCID: 0000-0003-2763-7004, Deshpande, Charu, Botia, Juan A, Reynolds, Regina H, Zhang, David, Simpson, Michael A
et al (show 136 more authors) (2019) Mitochondria function associated genes contribute to Parkinson's Disease risk and later age at onset. NPJ PARKINSONS DISEASE, 5.

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Resubmit.Genetic variation within genes associated with mitochondrial function is significantly associated with later age of onset of Parkinson disease and contributes to disease risk. KB - Google Docs.pdf - Accepted Version

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Abstract

Mitochondrial dysfunction has been implicated in the etiology of monogenic Parkinson’s disease (PD). Yet the role thatmitochondrial processes play in the most common form of the disease; sporadic PD, is yet to be fully established. Here, wecomprehensively assessed the role of mitochondrial function-associated genes in sporadic PD by leveraging improvements in thescale and analysis of PD GWAS data with recent advances in our understanding of the genetics of mitochondrial disease. Wecalculated a mitochondrial-specific polygenic risk score (PRS) and showed that cumulative small effect variants within both ourprimary and secondary gene lists are significantly associated with increased PD risk. We further reported that the PRS of thesecondary mitochondrial gene list was significantly associated with later age at onset. Finally, to identify possible functionalgenomic 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 genesare not only involved in mitophagy, but implicate new mitochondrial processes. Our data suggests that therapeutics targetingmitochondrial bioenergetics and proteostasis pathways distinct from mitophagy could be beneficial to treating the earlystage of PD.

Item Type: Article
Depositing User: Symplectic Admin
Date Deposited: 05 Jun 2019 08:36
Last Modified: 24 Nov 2020 05:10
DOI: 10.1038/s41531-019-0080-x
Related URLs:
URI: http://livrepository.liverpool.ac.uk/id/eprint/3043291