Deleterious heteroplasmic mitochondrial mutations increase risk of overall and cancer-specific mortality

Abstract

Mitochondria are involved in energetic, biosynthetic, and homeostatic processes in eukaryotic cells. Mitochondria carry their own circular genome and disruption of the quantity or quality of mitochondrial genome is associated with various aging – related diseases1 – 3. Unlike the nuclear genome, mitochondrial DNA (mtDNA) can be present at 1,000s to 10,000s copies in somatic cells and variants may exist in a state of heteroplasmy, where only a fraction of the DNA molecules harbor a particular variant. We used MitoHPC, a bioinformatics pipeline, to accurately quantify mtDNA heteroplasmy from whole genome sequencing data in 194,871 participants in the UK Biobank. We found that the presence of heteroplasmy is associated with an increased risk of all – cause mortality (adjusted hazard ratio [aHR] 1.50 – fold; 95% confidence interval [CI] 1.14, 1.98, when comparing participants with 4 or more heteroplasmies to those without any heteroplasmy). In addition, we functionally characterized mtDNA single nucleotide variants (SNVs) using a novel constraint – based score, Mitochondrial local constraint (MLC) score sum (MSS), which demonstrated that SNVs at highly constrained sites were strongly associated with all – cause mortality (aHR for a 1 – unit increase in MSS 1.28; 95% CI 1.20, 1.37) and cancer – related mortality (aHR 1.36; 95% CI 1.24,1.49), particularly lung and breast cancers, lymphoma, and leukemia. MSS was also associated with prevalence and incidence of lung cancer, lymphoma, and leukemia. Moreover, among individuals with prevalent leukemia, high MSS was strongly associated with leukemia mortality (adjusted HR 4.03; 95% CI 1.34, 12.11). These results indicate that mitochondria may have a functional role in certain cancers and mitochondrial heteroplasmic SNVs have the potential to serve as a prognostic markers for cancer incidence and outcome, especially for leukemia.

Quantifying constraint in the human mitochondrial genome

“…These results support different roles for mitochondria in neutrophils and platelets, with mtDNA likely playing a causal role in platelet count and non-causal role in neutrophil count, consistent with the lack of nuclear DNA in platelets and the diminished role of mitochondria in neutrophils (Supplementary Discussion). Further analysis revealed significant associations between MSS and other phenotypes, including mortality, as described in an accompanying manuscript 49 . These data support the utility of the MLC score, and provide examples of how these metrics can provide novel insight into the role of mtDNA variation in human phenotypes.…”

“…Mitochondrial heteroplasmy was identified from whole genome sequencing (WGS) data from the UK Biobank, a large population study of people from the United Kingdom aged 40-69 years 73 , as described previously 49 . In brief, MitoHPC 74 was used to call heteroplasmic SNVs with a heteroplasmy level of >5%.…”

“…Variants are heteroplasmic when they are in a fraction of mtDNA copies, or homoplasmic when found in all.Variants in the mtDNA can cause mitochondrial and cellular dysfunction, and accordingly have been linked to many human phenotypes. This includes causing rare mitochondrial diseases, which are clinically heterogeneous disorders causing 'any symptom, in any organ, at any age' 11 , as well as increasing the risk of common diseases such as autism 13 , cancer 14 , Alzheimer's and Parkinson's diseases 15 . Mitochondrial variation has also been linked to traits including glucose and insulin levels 16 , height 17 , and aging 18 .…”