Journal
NATURE GENETICS
Volume 53, Issue 7, Pages 982-+Publisher
NATURE RESEARCH
DOI: 10.1038/s41588-021-00868-1
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Funding
- UK Medical Research Council [MR/L003120/1]
- British Heart Foundation [RG/13/13/30194, RG/18/13/33946]
- NIHR Cambridge Biomedical Research Center [BRC-1215-20014]
- Health Data Research UK (UK Medical Research Council)
- Health Data Research UK (Engineering and Physical Sciences Research Council)
- Health Data Research UK (Economic and Social Research Council)
- Health Data Research UK (Department of Health and Social Care (England))
- Health Data Research UK (Chief Scientist Office of the Scottish Government Health and Social Care Directorates)
- Health Data Research UK (Health and Social Care Research and Development Division (Welsh Government))
- Health Data Research UK (Public Health Agency (Northern Ireland))
- Health Data Research UK (British Heart Foundation)
- Health Data Research UK (Wellcome)
- Wellcome Trust [212219/Z/18/Z]
- Medical Research Council Mitochondrial Biology Unit [MC_UU_00015/9]
- Medical Research Council International Center for Genomic Medicine in Neuromuscular Disease
- Evelyn Trust
- NIHR Cambridge BRC [BRC-1215-20014, 146281]
- Isaac Newton Trust/Wellcome Trust ISSF/University of Cambridge Joint Research Grants Scheme
- UKBB Resource [20480, 7439, 18794]
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This study explored the correlations between nuclear and mitochondrial genomic structures within subpopulations in Great Britain and established a UK Biobank reference atlas of mtDNA-phenotype associations. A total of 260 new mtDNA-phenotype associations were discovered, including variants linked to diseases and physiological characteristics.
Mitochondrial DNA (mtDNA) variation in common diseases has been underexplored, 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 subpopulations of Great Britain and establish a UK Biobank reference atlas of mtDNA-phenotype associations. A total of 260 mtDNA-phenotype associations were new (P < 1 x 10(-5)), including /m.8655 C>T (MT-ATP6) with type 2 diabetes, /m.13117 A>G (MT-ND5) with multiple sclerosis, 6 mtDNA associations with adult height, 24 mtDNA associations with 2 liver biomarkers and 16 mtDNA associations 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.
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