An atlas of mitochondrial DNA genotype-phenotype associations in the UK Biobank

@article{YonovaDoing2021AnAO,
  title={An atlas of mitochondrial DNA genotype-phenotype associations in the UK Biobank},
  author={Ekaterina Yonova-Doing and Claudia Calabrese and Aurora Gomez-Duran and Katherine R Schon and Wei Wei and Savita Karthikeyan and Patrick F. Chinnery and Joanna M. M. Howson},
  journal={Nature genetics},
  year={2021},
  volume={53},
  pages={982 - 993}
}
Mitochondrial genome (mtDNA) variation in common diseases has been under-explored, partly due to a lack of genotype calling and quality control procedures. Developing an at-scale workflow for mtDNA variant analyses, we show correlations between nuclear and mitochondrial genomic structures within sub-populations of Great Britain and establish a UK Biobank reference atlas of mtDNA-phenotype associations. A total of 260 mtDNA-phenotype associations were novel (P<1x10-5) including, rs2853822/m… 
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22 Citations
Highly Influential Citations
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Background Citations
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22 Citations

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TLDR
Exome data indicate strong-effect mutations from the nuclear genome contribute to the genetic architecture of mtDNA-CN, and rare variants were enriched in Mendelian mtDNA depletion syndrome loci, and these variants further implicated core processes in mtDNA replication, nucleoid structure formation, and maintenance.
A globally diverse reference alignment and panel for imputation of mitochondrial DNA variants
TLDR
Results show that a large, curated reference alignment and panel can be used to impute missing mtSNVs in existing data obtained from using microarrays, thereby broadening the scope of functional and clinical investigation of mtDNA.
Mitochondrial DNA variation across 56,434 individuals in gnomAD
TLDR
A pipeline to call mtDNA variants is presented that addresses three technical challenges: detecting homoplasmic and heteroplasic variants, present respectively in all or a fraction of mtDNA molecules, and misalignment of nuclear sequences of mitochondrial origin (NUMTs).
Interactions between nuclear and mitochondrial SNPs and Parkinson's disease risk
TLDR
Combinations of nuclear and mitochondrial variants affecting Parkinsons disease risk were identified from a single cohort design and showed significant evidence for an effect of the interaction between the mitochondrial and nuclear variants on disease risk.
Interactions between nuclear and mitochondrial SNPs and Parkinson’s disease risk
Exploring the Effects of Mitonuclear Interactions on Mitochondrial DNA Gene Expression in Humans
TLDR
It is demonstrated that, for most mtDNA protein-coding genes, expression levels in energetically-demanding tissues were lower in African Americans than in European Americans, and a negative correlation between mtDNA gene expression and mitonuclear discordance was found.
Blood Mitochondrial DNA Copy Number: What Are We Counting?
Examining the Association between Mitochondrial Genome Variation and Coronary Artery Disease
TLDR
Only spurious associations between MT genome variation and HARD/SOFT CAD are found and it is concluded that more MT- SNV data in even larger study cohorts may be needed to conclusively determine the role of MT-DNA in CAD.
Heteroplasmy of Wild-Type Mitochondrial DNA Variants in Mice Causes Metabolic Heart Disease With Pulmonary Hypertension and Frailty
TLDR
It is shown that DNPH impairs mitochondrial function, with profound consequences in critical tissues that cannot resolve heteroplasmy, particularly cardiac and skeletal muscle.
Changes of Gut Microbiota by Natural mtDNA Variant Differences Augment Susceptibility to Metabolic Disease and Ageing
TLDR
Both host gene expression and gut microbial changes caused by the mtDNA variant differences may contribute to the ageing and metabolic phenotypes observed in these mice strains, and identification of such mtDNA variants, specific gut bacterial species and bacterial metabolites may be a potential intervention to modulate common diseases.
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