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

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.8655C>T (MT-ATP6) with type 2 diabetes, rs878966690/m.13117A>G (MT-ND5) with multiple sclerosis, six mtDNA associations with adult height, 24 with two liver biomarkers and 16 with parameters of renal function. Rare variant gene-based tests implicated Complex I genes modulating mean corpuscular volume and mean corpuscular hemoglobin. Seven traits had both rare and common mtDNA associations where rare variants tended to have larger effects than common variants. Our work illustrates the value of studying mtDNA variants in common complex diseases and lays foundations for future large-scale mtDNA association studies.