Blood-derived mitochondrial DNA copy number is associated with gene expression across multiple tissues and is predictive for incident neurodegenerative disease

Abstract

Mitochondrial DNA copy number (mtDNA-CN) is a proxy for mitochondrial function and is associated with aging-related diseases. However, it is unclear how mtDNA-CN measured in blood can reflect diseases that primarily manifest in other tissues. Using the Genotype-Tissue Expression Project, we interrogated relationships between mtDNA-CN measured in whole blood and gene expression from whole blood and 47 additional tissues in 419 individuals. mtDNA-CN was significantly associated with expression of 700 genes in whole blood, including nuclear genes required for mtDNA replication. Significant enrichment was observed for splicing and ubiquitin-mediated proteolysis pathways, as well as target genes for the mitochondrial transcription factor NRF1. In nonblood tissues, there were more significantly associated genes than expected in 30 tissues, suggesting that global gene expression in those tissues is correlated with blood-derived mtDNA-CN. Neurodegenerative disease pathways were significantly associated in multiple tissues, and in an independent data set, the UK Biobank, we observed that higher mtDNA-CN was significantly associated with lower rates of both prevalent (OR = 0.89, CI = 0.83; 0.96) and incident neurodegenerative disease (HR = 0.95, 95% CI = 0.91;0.98). The observation that mtDNA-CN measured in blood is associated with gene expression in other tissues suggests that blood-derived mtDNA-CN can reflect metabolic health across multiple tissues. Identification of key pathways including splicing, RNA binding, and catalysis reinforces the importance of mitochondria in maintaining cellular homeostasis. Finally, validation of the role of mtDNA CN in neurodegenerative disease in a large independent cohort study solidifies the link between blood-derived mtDNA-CN, altered gene expression in multiple tissues, and aging-related disease.

Figure 1.

Global inflation of test statistics from linear regressions between blood-derived mtDNA-CN and gene expression in blood. After stratification by gene category, protein-coding genes have the most inflation, suggesting that mtDNA-CN is strongly associated with genes that code for proteins.

Figure 2.

REVIGO visualization of GO cellular component terms significantly associated with mtDNA-CN after removal of redundant GO terms. Size of the circle represents the relative number of genes in each gene set, color represents significance. Axes represent semantic similarities between GO terms; GO terms that are more similar will cluster with one another.

Figure 3.

Observed genomic inflation factors are significantly different from permuted genomic inflation factors for certain tissues. A higher genomic inflation factor represents increased global associations between blood-derived mtDNA-CN and gene expression in a specific tissue. One thousand permuted genomic inflation factors were obtained using two-stage permutation testing. Red line represents permuted lambda cutoff of 1.20.