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) can be used as a proxy for mitochondrial function and is associated with a number of aging-related diseases. However, it is unclear how mtDNA-CN measured in blood can reflect risk for diseases that primarily manifest in other tissues. Using the Genotype-Tissue Expression Project, we interrogated the relationships between mtDNA-CN measured in whole blood and gene expression from whole blood as well as 47 additional tissues. We evaluated associations between blood-derived mtDNA-CN and gene expression in whole blood for 418 individuals, correcting for known confounders and surrogate variables derived from RNA-sequencing. Using a permutation-derived cutoff (p<2.70e-6), mtDNA-CN was significantly associated with expression for 721 genes in whole blood, including nuclear genes that are required for mitochondrial DNA replication. Significantly enriched pathways included splicing (p=1.03e-8) and ubiquitin-mediated proteolysis (p=2.4e-10). Genes with target sequences for the mitochondrial transcription factor NRF1 were also enriched (p=1.76e-35). In non-blood tissues, there were more significantly associated genes than expected in 30 out of 47 tested tissues, suggesting that global gene expression in those tissues is correlated with mtDNA-CN. Pathways that were associated in multiple tissues included RNA-binding, catalysis, and neurodegenerative disease. We evaluated the association between mtDNA-CN and incident neurodegenerative disease in an independent dataset, the UK Biobank, using a Cox proportional-hazards model. Higher mtDNA-CN was significantly associated with lower risk for incident neurodegenerative disease (HR=0.73, 95% CI= 0.66;0.90). The observation that mtDNA-CN measured in whole blood is associated with gene expression in other tissues suggests that blood-derived mtDNA-CN can reflect metabolic health across multiple tissues. Key pathways in maintaining cellular homeostasis, including splicing, RNA binding, and catalytic genes were significantly associated with mtDNA-CN, reinforcing the importance of mitochondria in aging-related disease. As a specific example, genes involved in neurodegenerative disease were significantly enriched in multiple tissues. This finding, validated in a large independent cohort study showing an inverse association between mtDNA-CN and neurodegenerative disease, solidifies the link between blood-derived mtDNA-CN, altered gene expression in both blood and non-blood tissues, and aging-related disease.

Genetic analysis of mitochondrial DNA copy number and associated traits identifies loci implicated in nucleotide metabolism, platelet activation, and megakaryocyte proliferation, and reveals a causal association of mitochondrial function with mortality

“…chronic kidney disease 13 , heart failure 11 , and diabetes 75 ). Also consistent with this finding is recent work demonstrating that mtDNA-CN measured in blood is associated with mtRNA expression across numerous non-blood tissues, suggesting a link between mitochondrial function measured in blood and other tissues 76 .…”

“…We were able to identify a substantial proportion of the genes involved in mtDNA depletion syndromes (7/16, p = 3.09 × 10 −15 for enrichment), including TWNK, TFAM, DGUOK, MGME1, RRM2B, TYMP , and POLG . mtDNA depletion syndromes can be broken down into 5 subtypes based on their constellation of phenotypes 65 , and with the exception of cardiomyopathic subtypes (associated with mutations in AGK and SLC25A4 ), we were able to identify at least 1 gene from the other 4 subtypes, suggesting that our mtDNA-CN measurement in blood-derived DNA can identify genes widely relevant to non-blood phenotypes. This finding is consistent with a large body of work showing that mtDNA-CN measured in blood is associated with numerous aging-related phenotypes for which the primary tissue of interest is not blood (e.g.…”

“…Of particular interest, the GO term for amyloid beta is significantly enriched, reinforcing a link between mtDNA-CN and neurodegenerative disease [85][86][87] . Previous work from our lab using the UKB has shown that increased mtDNA-CN is associated with lower rates of prevalent neurodegenerative disease, and is predictive for decreased risk of incident neurodegenerative disease 76 . mtDNA-CN is also known to be decreased in the frontal cortex of Alzheimer's disease (AD) patients 88 .…”

Association of mitochondrial DNA copy number with cardiometabolic diseases in a large cross-sectional study of multiple ancestries

“…A recently study found that 23blood-derived mtDNA CN is associated with gene expression across multiple tissues and is predictive for incident neurodegenerative disease, which provides evidence supporting the hypothesis that changes in mtDNA in whole blood may reflect metabolic health across multiple systems. 51 Second, though we accounted for confounders and known batch effects in mtDNA CN and harmonized metabolic traits, we still observed moderate to high heterogeneity in the association coefficients in meta-analysis of most of the phenotypes in both ancestry-specific analyses and across ancestries. Different distributions of age, sex, and phenotypes across study cohorts may partially explain the heterogeneity in these associations.…”

Characterization of mitochondrial DNA quantity and quality in the human aged and Alzheimer’s disease brain

“…Similar results were reported for other neurodegenerative diseases (Filograna et al, 2020). Interestingly, although mtDNAcn derived from whole blood is often confounded by variation in cell type composition between individuals, a recent study found an association with AD suggesting that the mtDNAcn in whole blood could potentially reflect metabolic health across tissues (Yang et al, 2021). While the mtDNAcn overall seems to be reduced in brain regions affected by neurodegenerative diseases, mixed results have been reported for the effect of aging on mtDNAcn.…”