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

19 p.-7 fig.-4 tab.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 T (MT-ATP6) with type 2 diabetes, rs878966690/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.The BHF Cardiovascular Epidemiology Unit is supported by the UK Medical Research Council (MR/L003120/1), British Heart Foundation (RG/13/13/30194 and RG/18/13/33946) and the NIHR Cambridge Biomedical Research Center (BRC-1215-20014) and Health Data Research UK (which is funded by the UK Medical Research Council, Engineering and Physical Sciences Research Council, Economic and Social Research Council, Department of Health and Social Care (England), Chief Scientist Office of the Scottish Government Health and Social Care Directorates, Health and Social Care Research and Development Division (Welsh Government), Public Health Agency (Northern Ireland), British Heart Foundation and Wellcome). P.C. is a Wellcome Trust Principal Research Fellow (212219/Z/18/Z) and a UK NIHR senior investigator, who receives support from the Medical Research Council Mitochondrial Biology Unit (MC_UU_00015/9), the Medical Research Council International Center for Genomic Medicine in Neuromuscular Disease, the Evelyn Trust and the NIHR Cambridge BRC (BRC-1215-20014) [*]. J.H. is funded by the British Heart Foundation (RG/13/13/30194) and the NIHR Cambridge BRC (BRC-1215-20014) [*]. E.Y.-D. was funded by the Isaac Newton Trust/Wellcome Trust ISSF/University of Cambridge Joint Research Grants Scheme. A.G.-D. is funded by the NIHR Cambridge BRC (146281)