Mitochondria function associated genes contribute to Parkinson\u2019s Disease risk and later age at onset

Billingsley Kj ,Ning Ma ,David Zhang ,Cornelis Blauwendraat ,Mina Ryten ,Andrew Singleton ,Ziv Gan‐Or ,J Raphael Gibbs ,Bubb Vj ,Jp Quinn ,Sara Bandrés‐Ciga ,Barbosa Ia ,Botía Ja ,Regina H Reynolds ,Michael A Simpson ,Charu Deshpande ,Sulev Kõks

doi:10.1038/s41531-019-0080-x

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.

Highlights

Parkinson’s disease (PD) is a progressive neurodegenerative movement disorder characterized pathologically by the death of dopaminergic neurons in the substantia nigra (SN) and aggregation of α-synuclein protein, within intraneuronal inclusions called Lewy bodies
The construction of this annotation was driven by the principle that genomic regions, which are known to be the sites of mutations in individuals with rare mitochondrial diseases or are candidate regions for such mutations provide the best evidence for involvement in mitochondrial function
Consistent with previous heritability estimates from both Keller et al(24%) and Chang et al (21%), our random-effects meta-analysis for the four datasets identified 23% phenotypic variance associated with all PD samples (Tables 1 and 2)

Summary

Introduction

Parkinson’s disease (PD) is a progressive neurodegenerative movement disorder characterized pathologically by the death of dopaminergic neurons in the substantia nigra (SN) and aggregation of α-synuclein protein (encoded by SNCA), within intraneuronal inclusions called Lewy bodies. The majority of PD cases are apparently sporadic in nature (~95%). Aging is a major risk factor for disease and due to population ageing the prevalence of PD is predicted to increase rapidly, making the identification of therapeutic targets a high priority.[1–3]. There have been great advances in understanding both the genetic architecture and cellular processes involved in PD, the exact molecular mechanisms that underlie PD remain unknown.[1]. It is suggested that PD has a complex etiology, involving several molecular pathways, and understanding these specific pathways will be key to establishing mechanistic targets for therapeutic intervention. While several key pathways are currently being investigated, including autophagy, endocytosis, immune response, and lysosomal function,[4–7] mitochondrial function was the first biological process to be associated with PD.[8,9]

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Results

Conclusion