Association between mitochondrial DNA copy number and the risk of Parkinson’s disease: a meta-analysis and Mendelian randomization study

Parkinson’s disease (PD) is a common neurodegenerative disorder characterized by both motor and non-motor symptoms, with mitochondrial dysfunction being a key pathological feature. Alterations in mitochondrial DNA copy number (mtDNA-CN) have been implicated in PD, but the relationship remains controversial. This study aimed to investigate the association between mtDNA-CN and PD through a meta-analysis and Mendelian randomization (MR) analysis to assess the potential causality. To investigate the relationship between mtDNA-CN and PD, a comprehensive literature search was conducted across PubMed, Scopus, Web of Science, CNKI, and Wan Fang databases. Studies meeting predefined inclusion and exclusion criteria were selected, and a meta-analysis was performed to quantitatively synthesize the effect sizes. To further evaluate the potential causal association between mtDNA-CN and PD risk, MR analysis was conducted using genetic variants associated with mtDNA-CN as instrumental variables. Summary-level data were obtained from publicly available genome-wide association study (GWAS) datasets, including the IEU Open GWAS and FinnGen consortia. These analyses aimed to provide robust evidence regarding the potential causal role of mtDNA-CN in the pathophysiology of PD. Thirteen studies meeting the inclusion criteria were included in the meta-analysis. A significant association was identified between reduced mtDNA-CN in cerebrospinal fluid and an increased risk of PD. However, no significant association was observed between mtDNA-CN levels in blood and PD risk. Additionally, although mtDNA deletion levels were slightly elevated in PD patients compared to controls, this difference did not reach statistical significance. MR analysis, based on aggregated data from the IEU Open GWAS and FinnGen datasets, did not support a causal relationship between mtDNA-CN and PD risk (p = 0.78). The robustness and consistency of the MR results were confirmed by Egger’s test and sensitivity analyses. This study suggests that mtDNA-CN in cerebrospinal fluid holds potential clinical utility as a biomarker for PD. While further validation is needed, these findings contribute to a growing understanding of mitochondrial dysfunction in neurodegeneration and may offer new avenues for improving the diagnosis and management of PD.