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

Abstract

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.

Comprehensive summary of mitochondrial DNA alterations in the postmortem human brain: A systematic review

“… 84 However, the association of homoplasmic common and rare SNV on longevity and NeuD such as multiple sclerosis has been recently confirmed by analysing a large number of blood samples. 32 An interesting study that also investigated blood samples demonstrates the involvement of the nuclear female genome in the evolution of human mtDNA variation and also suggests the different values of heteroplasmy that an individual cell, tissue or organism may exhibit during embryonic development of human germ cells. 163 The different expansion of heteroplasmic variants during the ageing process could have consequences for age-associated diseases such as NeuD but also PsyD, which present in many cases within certain age ranges.…”

“…This is supported by the recent success in identifying associations between a large number of phenotypes and homoplasmic mtDNA variants by analysing a large number of blood samples from the UK Biobank. 32 In summary, most studies that explored mtDNA alterations in neurological diseases, mental illnesses and the natural ageing process have reported conflicting results. Some reasons for this are that different studies have investigated different mtDNA alterations, different diagnoses and/or different brain regions.…”

“…Notably, this study identified a key role for mtDNA common and rare SNV variation (only homoplasmic) in many quantitative human traits and disease risks, with a particular emphasis on cardiometabolic and neurodegenerative diseases. 32 mtDNA pSNVs can be observed in homoplasmy or heteroplasmy, while mtDNA deletions are always heteroplasmic, since within the deleted region, mtDNA consistently contain one or more tRNAs indispensable for the translation of the protein-associated mtDNA genes, which are essential for life. Known mtDNA pSNVs lead to syndromes such as mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS), myoclonic epilepsy with ragged red fibres (MERRF), neuropathy, ataxia and retinitis pigmentosa (NARP), and Leigh syndrome (LS).…”

From Forensics to Clinical Research: Expanding the Variant Calling Pipeline for the Precision ID mtDNA Whole Genome Panel

“…Although sometimes ignored [ 50 ], heteroplasmic variants are ubiquitous [ 51 , 52 , 53 , 54 ] and show significant tissue-specificity [ 53 , 54 ]. Interestingly, low-level heteroplasmic variants (VL <10%) have shown matrilineal inheritance [ 55 , 56 ] with increased relevance in aging [ 57 ], and in clinical settings, particularly cancer [ 58 , 59 ].…”

Gaining Insight into Mitochondrial Genetic Variation and Downstream Pathophysiology: What Can i(PSCs) Do?

“…Mitochondrial respiratory chain disorders, often with diverse clinical presentations, affect an estimated 1 in 4300 individuals [3,4]. Pathogenic mutations may arise in either genome and result in defective OXPHOS, which drives alterations in upstream metabolic pathways.…”